|
1
|
Mansouri RA, Aboubakr EM, Alshaibi HF, Ahmed AM. L-arginine administration exacerbates myocardial injury in diabetics via prooxidant and proinflammatory mechanisms along with myocardial structural disruption. World J Diabetes 2025; 16:100395. [PMID: 39959273 PMCID: PMC11718468 DOI: 10.4239/wjd.v16.i2.100395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 10/02/2024] [Accepted: 11/25/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND L-arginine (L-Arg) is one of the most widely used amino acids in dietary and pharmacological products. However, the evidence on its usefulness and dose limitations, especially in diabetics is still controversial. AIM To investigate the effects of chronic administration of different doses of L-Arg on the cardiac muscle of type 2 diabetic rats. METHODS Of 96 male rats were divided into 8 groups as follows (n = 12): Control, 0.5 g/kg L-Arg, 1 g/kg L-Arg, 1.5 g/kg L-Arg, diabetic, diabetic + 0.5 g/kg L-Arg, diabetic + 1 g/kg L-Arg, and diabetic + 1.5 g/kg L-Arg; whereas L-Arg was orally administered for 3 months to all treated groups. RESULTS L-Arg produced a moderate upregulation of blood glucose levels to normal rats, but when given to diabetics a significant upregulation was observed, associated with increased nitric oxide, inflammatory cytokines, and malonaldehyde levels in diabetic rats treated with 1 g/kg L-Arg and 1.5 g/kg L-Arg. A substantial decrease in the antioxidant capacity, superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione concentrations, and Nrf-2 tissue depletion were observed at 1 g/kg and 1.5 g/kg L-Arg diabetic treated groups, associated with myocardial injury, fibrosis, α-smooth muscle actin upregulation, and disruption of desmin cardiac myofilaments, and these effects were not noticeable at normal treated groups. On the other hand, L-Arg could significantly improve the lipid profile of diabetic rats and decrease their body weights. CONCLUSION L-Arg dose of 1 g/kg or more can exacerbates the diabetes injurious effects on the myocardium, while 0.5 g/kg dose can improve the lipid profile and decrease the body weight.
Collapse
Affiliation(s)
- Rasha A Mansouri
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 22254, Jeddah, Saudi Arabia
- College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Esam M Aboubakr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy-South Valley University, Qena 83523, Egypt
| | - Huda F Alshaibi
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 22254, Jeddah, Saudi Arabia
- Stem Cell Unit, King Fahad Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Adel M Ahmed
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, South Valley University, Qena 83523, Egypt
| |
Collapse
|
|
2
|
Chim SM, Howell K, Dronzek J, Wu W, Van Hout C, Ferreira MAR, Ye B, Li A, Brydges S, Arunachalam V, Marcketta A, Locke AE, Bovijn J, Verweij N, De T, Lotta L, Mitnaul L, LeBlanc M, Center RG, Carey DJ, Melander O, Shuldiner A, Karalis K, Economides AN, Nistala H. Genetic inactivation of zinc transporter SLC39A5 improves liver function and hyperglycemia in obesogenic settings. eLife 2024; 12:RP90419. [PMID: 39671241 DOI: 10.7554/elife.90419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2024] Open
Abstract
Recent studies have revealed a role for zinc in insulin secretion and glucose homeostasis. Randomized placebo-controlled zinc supplementation trials have demonstrated improved glycemic traits in patients with type II diabetes (T2D). Moreover, rare loss-of-function variants in the zinc efflux transporter SLC30A8 reduce T2D risk. Despite this accumulated evidence, a mechanistic understanding of how zinc influences systemic glucose homeostasis and consequently T2D risk remains unclear. To further explore the relationship between zinc and metabolic traits, we searched the exome database of the Regeneron Genetics Center-Geisinger Health System DiscovEHR cohort for genes that regulate zinc levels and associate with changes in metabolic traits. We then explored our main finding using in vitro and in vivo models. We identified rare loss-of-function (LOF) variants (MAF <1%) in Solute Carrier Family 39, Member 5 (SLC39A5) associated with increased circulating zinc (p=4.9 × 10-4). Trans-ancestry meta-analysis across four studies exhibited a nominal association of SLC39A5 LOF variants with decreased T2D risk. To explore the mechanisms underlying these associations, we generated mice lacking Slc39a5. Slc39a5-/- mice display improved liver function and reduced hyperglycemia when challenged with congenital or diet-induced obesity. These improvements result from elevated hepatic zinc levels and concomitant activation of hepatic AMPK and AKT signaling, in part due to zinc-mediated inhibition of hepatic protein phosphatase activity. Furthermore, under conditions of diet-induced non-alcoholic steatohepatitis (NASH), Slc39a5-/- mice display significantly attenuated fibrosis and inflammation. Taken together, these results suggest SLC39A5 as a potential therapeutic target for non-alcoholic fatty liver disease (NAFLD) due to metabolic derangements including T2D.
Collapse
Affiliation(s)
| | | | - John Dronzek
- Regeneron Genetics Center, New York, United States
| | - Weizhen Wu
- Regeneron Genetics Center, New York, United States
| | | | | | - Bin Ye
- Regeneron Genetics Center, New York, United States
| | - Alexander Li
- Regeneron Genetics Center, New York, United States
| | | | | | | | - Adam E Locke
- Regeneron Genetics Center, New York, United States
| | - Jonas Bovijn
- Regeneron Genetics Center, New York, United States
| | - Niek Verweij
- Regeneron Genetics Center, New York, United States
| | - Tanima De
- Regeneron Genetics Center, New York, United States
| | - Luca Lotta
- Regeneron Genetics Center, New York, United States
| | | | | | | | | | | | | | | | - Aris N Economides
- Regeneron Genetics Center, New York, United States
- Regeneron Pharmaceuticals, New York, United States
| | | |
Collapse
|
|
3
|
Jimenez V, Sacristan V, Jambrina C, Jaen ML, Casana E, Muñoz S, Marcó S, Molas M, Garcia M, Grass I, León X, Elias I, Ribera A, Elias G, Sanchez V, Vilà L, Casellas A, Ferre T, Rodó J, Carretero A, Pumarola M, Navarro M, Andaluz A, Moll X, Añor S, Franckhauser S, Vergara M, Caixàs A, Bosch F. Reversion of metabolic dysfunction-associated steatohepatitis by skeletal muscle-directed FGF21 gene therapy. Mol Ther 2024; 32:4285-4302. [PMID: 39489916 PMCID: PMC11638876 DOI: 10.1016/j.ymthe.2024.10.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 09/25/2024] [Accepted: 10/23/2024] [Indexed: 11/05/2024] Open
Abstract
The highly prevalent metabolic dysfunction-associated steatohepatitis (MASH) is associated with liver steatosis, inflammation, and hepatocyte injury, which can lead to fibrosis and may progress to hepatocellular carcinoma and death. New treatment modalities such as gene therapy may be transformative for MASH patients. Here, we describe that one-time intramuscular administration of adeno-associated viral vectors of serotype 1 (AAV1) encoding native fibroblast growth factor 21 (FGF21), a key metabolic regulator, resulted in sustained increased circulating levels of the factor, which mediated long-term (>1 year) MASH and hepatic fibrosis reversion and halted development of liver tumors in obese male and female mouse models. AAV1-FGF21 treatment also counteracted obesity, adiposity, and insulin resistance, which are significant drivers of MASH. Scale-up to large animals successfully resulted in safe skeletal muscle biodistribution and biological activity in key metabolic tissues. Moreover, as a step toward the clinic, circulating FGF21 levels were characterized in obese, insulin-resistant and MASH patients. Overall, these results underscore the potential of the muscle-directed AAV1-FGF21 gene therapy to treat MASH and support its clinical translation.
Collapse
Affiliation(s)
- Veronica Jimenez
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Victor Sacristan
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Claudia Jambrina
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Maria Luisa Jaen
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Estefania Casana
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Sergio Muñoz
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Sara Marcó
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Maria Molas
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Miquel Garcia
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Ignasi Grass
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Xavier León
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Ivet Elias
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Albert Ribera
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Gemma Elias
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Victor Sanchez
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Laia Vilà
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Alba Casellas
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Tura Ferre
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Jordi Rodó
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Ana Carretero
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Marti Pumarola
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Animal Medicine and Surgery, School of Veterinary Medicine, Universitat Autònoma Barcelona, 08193 Bellaterra, Spain
| | - Marc Navarro
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Anna Andaluz
- Department of Animal Medicine and Surgery, School of Veterinary Medicine, Universitat Autònoma Barcelona, 08193 Bellaterra, Spain
| | - Xavier Moll
- Department of Animal Medicine and Surgery, School of Veterinary Medicine, Universitat Autònoma Barcelona, 08193 Bellaterra, Spain
| | - Sonia Añor
- Department of Animal Medicine and Surgery, School of Veterinary Medicine, Universitat Autònoma Barcelona, 08193 Bellaterra, Spain
| | - Sylvie Franckhauser
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Mercedes Vergara
- Institut d'Investigació i Innovació Parc Taulí (I3PT-CERCA), 08202 Sabadell, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Teaching Unit Parc Taulí, 08202 Sabadell, Spain; Department of Hepatology, Digestive Service, Hospital Universitari Parc Taulí, 08202 Sabadell, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
| | - Assumpta Caixàs
- Institut d'Investigació i Innovació Parc Taulí (I3PT-CERCA), 08202 Sabadell, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Teaching Unit Parc Taulí, 08202 Sabadell, Spain; Department of Endocrinology and Nutrition, Hospital Universitari Parc Taulí, 08202 Sabadell, Spain
| | - Fatima Bosch
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain.
| |
Collapse
|
|
4
|
Donis C, Fauste E, Pérez-Armas M, Otero P, Panadero MI, Bocos C. Cardiac Hypertrophy in Pregnant Rats, Descendants of Fructose-Fed Mothers, an Effect That Worsens with Fructose Supplementation. Foods 2024; 13:2944. [PMID: 39335874 PMCID: PMC11431301 DOI: 10.3390/foods13182944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/10/2024] [Accepted: 09/14/2024] [Indexed: 09/30/2024] Open
Abstract
The role of fructose consumption in the development of obesity, MetS, and CVD epidemic has been widely documented. Notably, among other effects, fructose consumption has been demonstrated to induce cardiac hypertrophy. Moreover, fructose intake during pregnancy can cause hypertrophy of the maternal heart. Our previous research has demonstrated that maternal fructose intake has detrimental effects on fetuses, which persist into adulthood and are exacerbated upon re-exposure to fructose. Additionally, we found that maternal fructose consumption produces changes in female progeny that alter their own pregnancy. Despite these findings, fructose intake during pregnancy is not currently discouraged. Given that cardiac hypertrophy is a prognostic marker for heart disease and heart failure, this study aimed to determine whether metabolic changes occurring during pregnancy in the female progeny of fructose-fed mothers could provoke a hypertrophic heart. To test this hypothesis, pregnant rats from fructose-fed mothers, with (FF) and without (FC) fructose supplementation, were studied and compared to pregnant control rats (CC). Maternal hearts were analyzed. Although both FF and FC mothers exhibited heart hypertrophy compared to CC rats, cardiac DNA content was more diminished in the hearts of FF dams than in those of FC rats, suggesting a lower number of heart cells. Accordingly, changes associated with cardiac hypertrophy, such as HIF1α activation and hyperosmolality, were observed in both the FC and FF dams. However, FF dams also exhibited higher oxidative stress, lower autophagy, and decreased glutamine protection against hypertrophy than CC dams. In conclusion, maternal fructose intake induces changes in female progeny that alter their own pregnancy, leading to cardiac hypertrophy, which is further exacerbated by subsequent fructose intake.
Collapse
Affiliation(s)
- Cristina Donis
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, 28668 Madrid, Spain
| | - Elena Fauste
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, 28668 Madrid, Spain
| | - Madelín Pérez-Armas
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, 28668 Madrid, Spain
| | - Paola Otero
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, 28668 Madrid, Spain
| | - María I Panadero
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, 28668 Madrid, Spain
| | - Carlos Bocos
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, 28668 Madrid, Spain
| |
Collapse
|
|
5
|
Seessle J, Liebisch G, Staffer S, Tuma-Kellner S, Merle U, Herrmann T, Chamulitrat W. Enterocyte-specific FATP4 deficiency elevates blood lipids via a shift from polar to neutral lipids in distal intestine. Am J Physiol Gastrointest Liver Physiol 2024; 327:G202-G216. [PMID: 38915276 DOI: 10.1152/ajpgi.00109.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 06/13/2024] [Accepted: 06/20/2024] [Indexed: 06/26/2024]
Abstract
Fatty acid transport protein (FATP)4 was thought to mediate intestinal lipid absorption, which was disputed by a study using keratinocyte-Fatp4-rescued Fatp4-/- mice. These knockouts when fed with a Western diet showed elevated intestinal triglyceride (TG) and fatty acid levels. To investigate a possible role of FATP4 on intestinal lipid processing, ent-Fatp4 (KO) mice were generated by Villin-Cre-specific inactivation of the Fatp4 gene. We aimed to measure circulating and intestinal lipids in control and KO mice after acute or chronic fat intake or during aging. Remarkably, ent-Fatp4 mice displayed an approximately 30% decrease in ileal behenic, lignoceric, and nervonic acids, ceramides containing these FA, as well as, ileal sphingomyelin, phosphatidylcholine, and phosphatidylinositol levels. Such decreases were concomitant with an increase in jejunal cholesterol ester. After a 2-wk recovery from high lipid overload by tyloxapol and oral-lipid treatment, ent-Fatp4 mice showed an increase in plasma TG and chylomicrons. Upon overnight fasting followed by an oral fat meal, ent-Fatp4 mice showed an increase in plasma TG-rich lipoproteins and the particle number of chylomicrons and very low-density lipoproteins. During aging or after feeding with a high-fat high-cholesterol (HFHC) diet, ent-Fatp4 mice showed an increase in plasma TG, fatty acids, glycerol, and lipoproteins as well as intestinal lipids. HFHC-fed KO mice displayed an increase in body weight, the number of lipid droplets with larger sizes in the ileum, concomitant with a decrease in ileal ceramides and phosphatidylcholine. Thus, enterocyte FATP4 deficiency led to a metabolic shift from polar to neutral lipids in distal intestine rendering an increase in plasma lipids and lipoproteins.NEW & NOTEWORTHY Enterocyte-specific Fatp4 deficiency in mice increased intestinal lipid absorption with elevation of blood lipids during fasting and aging, as well as after an acute oral fat-loading or chronic HFHC feeding. Lipidomics revealed that knockout mice displayed a shift from very long-chain to long-chain fatty acids, and from polar to neutral lipids, predominantly in the ileum. Thus, FATP4 may have a physiological function in the control of blood lipids via metabolic shifts in distal intestine.
Collapse
Affiliation(s)
- Jessica Seessle
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany
| | - Simone Staffer
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Sabine Tuma-Kellner
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Uta Merle
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas Herrmann
- Department of Medical Clinic 1, Westkuesten Hospital, Heide, Germany
| | - Walee Chamulitrat
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| |
Collapse
|
|
6
|
Jang H, Woo H, Corvino O, Kang H, Kim MB, Lee JY, Park YK. Dietary sugar kelp ( Saccharina latissima) consumption did not attenuate atherosclerosis in low-density lipoprotein receptor knockout mice. Food Funct 2024; 15:6684-6691. [PMID: 38819217 DOI: 10.1039/d4fo01037j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2024]
Abstract
We previously demonstrated the beneficial effects of U.S.-grown sugar kelp (Saccharina latissima), a brown seaweed, on reducing serum triglycerides (TG) and total cholesterol (TC) and protecting against inflammation and fibrosis in the adipose tissue of diet-induced obesity mice. In this current study, we aimed to explore whether the dietary consumption of sugar kelp can prevent atherosclerosis using low-density lipoprotein receptor knockout (Ldlr KO) mice fed an atherogenic diet. Eight-week-old male Ldlr KO mice were fed either an atherogenic high-fat/high-cholesterol control (HF/HC) diet or a HF/HC diet supplemented with 6% (w/w) sugar kelp (HF/HC-SK) for 16 weeks. Consumption of sugar kelp significantly increased the body weight gain without altering fat mass and lean mass. Also, there were no significant differences in energy expenditure and physical activities between the groups. The two groups did not show significant differences in serum and hepatic TG and TC levels or the hepatic expression of genes involved in cholesterol and lipid metabolism. Although serum alanine aminotransferase (ALT) activity did not differ significantly between the two groups, there were significant increases in the expression of macrophage markers, including adhesion G protein-coupled receptor E1 and cluster of differentiation 68, as well as tumor necrosis factor alpha in the HF/HC-SK group compared to the HF/HC mice. The consumption of sugar kelp did not elicit a significant effect on the development of aortic lesions. Moreover, lipopolysaccharide-stimulated splenocytes isolated from HF/HC-SK-fed mice showed no significant changes in the mRNA levels of pro-inflammatory genes compared with those from the HF/HC mice. In summary, the consumption of dietary sugar kelp did not elicit anti-atherogenic and hepatoprotective effects in Ldlr KO mice.
Collapse
Affiliation(s)
- Hyungryun Jang
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, 27 Manter Rd, Storrs, CT 06269, USA.
| | - Hayoung Woo
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, 27 Manter Rd, Storrs, CT 06269, USA.
| | - Olivia Corvino
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, 27 Manter Rd, Storrs, CT 06269, USA.
| | - Hyunju Kang
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, 27 Manter Rd, Storrs, CT 06269, USA.
- Department of Food and Nutrition, Keimyung University, Daegu, South Korea
| | - Mi-Bo Kim
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, 27 Manter Rd, Storrs, CT 06269, USA.
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, 27 Manter Rd, Storrs, CT 06269, USA.
| | - Young-Ki Park
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, 27 Manter Rd, Storrs, CT 06269, USA.
| |
Collapse
|
|
7
|
Fauste E, Panadero MI, Pérez-Armas M, Donis C, López-Laiz P, Sevillano J, Sánchez-Alonso MG, Ramos-Álvarez MP, Otero P, Bocos C. Maternal fructose intake aggravates the harmful effects of a Western diet in rat male descendants impacting their cholesterol metabolism. Food Funct 2024; 15:6147-6163. [PMID: 38767501 DOI: 10.1039/d4fo01466a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Scope: fructose consumption from added sugars correlates with the epidemic rise in MetS and CVD. Maternal fructose intake has been described to program metabolic diseases in progeny. However, consumption of fructose-containing beverages is allowed during gestation. Cholesterol is also a well-known risk factor for CVD. Therefore, it is essential to study Western diets which combine fructose and cholesterol and how maternal fructose can influence the response of progeny to these diets. Methods and results: a high-cholesterol (2%) diet combined with liquid fructose (10%), as a model of an unhealthy Western diet, was administered to descendants from control and fructose-fed mothers. Gene (mRNA and protein) expression and plasma, fecal and tissue parameters of cholesterol metabolism were measured. Interestingly, progeny from fructose-fed dams consumed less liquid fructose and cholesterol-rich chow than males from control mothers. Moreover, descendants of fructose-fed mothers fed a Western diet showed an increased cholesterol elimination through bile and feces than males from control mothers. Despite these mitigating circumstances to develop a proatherogenic profile, the same degree of hypercholesterolemia and severity of steatosis were observed in all descendants fed a Western diet, independently of maternal intake. An increased intestinal absorption of cholesterol, synthesis, esterification, and assembly into lipoprotein found in males from fructose-fed dams consuming a Western diet could be the cause. Moreover, an augmented GLP2 signalling seen in these animals would explain this enhanced lipid absorption. Conclusions: maternal fructose intake, through a fetal programming, makes a Western diet considerably more harmful in their descendants than in the offspring from control mothers.
Collapse
Affiliation(s)
- E Fauste
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, Madrid, Spain.
| | - M I Panadero
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, Madrid, Spain.
| | - M Pérez-Armas
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, Madrid, Spain.
| | - C Donis
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, Madrid, Spain.
| | - P López-Laiz
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, Madrid, Spain.
| | - J Sevillano
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, Madrid, Spain.
| | - M G Sánchez-Alonso
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, Madrid, Spain.
| | - M P Ramos-Álvarez
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, Madrid, Spain.
| | - P Otero
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, Madrid, Spain.
| | - C Bocos
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, Madrid, Spain.
| |
Collapse
|
|
8
|
Higuchi M, Okumura M, Mitsuta S, Shirouchi B. Dietary Cholest-4-en-3-one, a Cholesterol Metabolite of Gut Microbiota, Alleviates Hyperlipidemia, Hepatic Cholesterol Accumulation, and Hyperinsulinemia in Obese, Diabetic db/db Mice. Metabolites 2024; 14:321. [PMID: 38921456 PMCID: PMC11205736 DOI: 10.3390/metabo14060321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 05/30/2024] [Accepted: 05/31/2024] [Indexed: 06/27/2024] Open
Abstract
Previous studies have shown that dietary cholest-4-en-3-one (4-cholestenone, 4-STN) exerts anti-obesity and lipid-lowering effects in mice. However, its underlying mechanisms are not fully understood. In the present study, we evaluated whether 4-STN supplementation would protect obese diabetic db/db mice from obesity-related metabolic disorders. After four weeks of feeding of a 0.25% 4-STN-containing diet, dietary 4-STN was found to have significantly alleviated hyperlipidemia, hepatic cholesterol accumulation, and hyperinsulinemia; however, the effect was not sufficient to improve hepatic triglyceride accumulation or obesity. Further analysis demonstrated that dietary 4-STN significantly increased the content of free fatty acids and neutral steroids in the feces of db/db mice, indicating that the alleviation of hyperlipidemia by 4-STN was due to an increase in lipid excretion. In addition, dietary 4-STN significantly reduced the levels of desmosterol, a cholesterol precursor, in the plasma but not in the liver, suggesting that normalization of cholesterol metabolism by 4-STN is partly attributable to the suppression of cholesterol synthesis in extrahepatic tissues. In addition, dietary 4-STN increased the plasma and hepatic levels of 4-STN metabolites cholestanol (5α-cholestan-3β-ol) and coprostanol (5β-cholestan-3β-ol). Our results show that dietary 4-STN alleviates obesity-related metabolic disorders, such as hyperlipidemia, hepatic cholesterol accumulation, and hyperinsulinemia, in db/db mice.
Collapse
Affiliation(s)
- Mina Higuchi
- Nutrition Science Course, Division of Human Health Science, Graduate School of Regional Design and Creation, University of Nagasaki, Siebold, 1-1-1 Manabino, Nagayo-cho, Nishi-Sonogi-gun, Nagasaki 851-2195, Japan
| | - Mai Okumura
- Nutrition Science Course, Division of Human Health Science, Graduate School of Regional Design and Creation, University of Nagasaki, Siebold, 1-1-1 Manabino, Nagayo-cho, Nishi-Sonogi-gun, Nagasaki 851-2195, Japan
| | - Sarasa Mitsuta
- Nutrition Science Course, Division of Human Health Science, Graduate School of Regional Design and Creation, University of Nagasaki, Siebold, 1-1-1 Manabino, Nagayo-cho, Nishi-Sonogi-gun, Nagasaki 851-2195, Japan
| | - Bungo Shirouchi
- Nutrition Science Course, Division of Human Health Science, Graduate School of Regional Design and Creation, University of Nagasaki, Siebold, 1-1-1 Manabino, Nagayo-cho, Nishi-Sonogi-gun, Nagasaki 851-2195, Japan
- Department of Nutrition Science, Faculty of Nursing and Nutrition, University of Nagasaki, Siebold, 1-1-1 Manabino, Nagayo-cho, Nishi-Sonogi-gun, Nagasaki 851-2195, Japan
| |
Collapse
|
|
9
|
López de Las Hazas MC, Del Saz-Lara A, Cedó L, Crespo MC, Tomé-Carneiro J, Chapado LA, Macià A, Visioli F, Escola-Gil JC, Dávalos A. Hydroxytyrosol Induces Dyslipidemia in an ApoB100 Humanized Mouse Model. Mol Nutr Food Res 2024; 68:e2300508. [PMID: 37933702 DOI: 10.1002/mnfr.202300508] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/25/2023] [Indexed: 11/08/2023]
Abstract
SCOPE Extra virgin olive oil has numerous cardiopreventive effects, largely due to its high content of (poly)phenols such as hydroxytyrosol (HT). However, some animal studies suggest that its excessive consumption may alter systemic lipoprotein metabolism. Because human lipoprotein metabolism differs from that of rodents, this study examines the effects of HT in a humanized mouse model that approximates human lipoprotein metabolism. METHODS AND RESULTS Mice are treated as follows: control diet or diet enriched with HT. Serum lipids and lipoproteins are determined after 4 and 8 weeks. We also analyzed the regulation of various genes and miRNA by HT, using microarrays and bioinformatic analysis. An increase in body weight is found after supplementation with HT, although food intake was similar in both groups. In addition, HT induced the accumulation of triacylglycerols but not cholesterol in different tissues. Systemic dyslipidemia after HT supplementation and impaired glucose metabolism are observed. Finally, HT modulates the expression of genes related to lipid metabolism, such as Pltp or Lpl. CONCLUSION HT supplementation induces systemic dyslipidemia and impaired glucose metabolism in humanized mice. Although the numerous health-promoting effects of HT far outweigh these potential adverse effects, further carefully conducted studies are needed.
Collapse
Affiliation(s)
- María-Carmen López de Las Hazas
- Laboratory of Epigenetics of Lipid Metabolism, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, CEI UAM+CSIC, Madrid, 28049, Spain
| | - Andrea Del Saz-Lara
- Laboratory of Epigenetics of Lipid Metabolism, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, CEI UAM+CSIC, Madrid, 28049, Spain
- Laboratory of Functional Foods, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, CEI UAM+CSIC, Madrid, 28049, Spain
- Health and Social Research Center, Universidad de Castilla-La Mancha, Cuenca, 16171, Spain
| | - Lídia Cedó
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, 08041, Spain
- Department of Endocrinology and Nutrition, Research Unit, Institut d'Investigació Sanitària Pere Virgili (IISPV), Hospital Universitari de Tarragona Joan XXIII, Tarragona, 43005, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain
| | - María Carmen Crespo
- Laboratory of Functional Foods, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, CEI UAM+CSIC, Madrid, 28049, Spain
| | - João Tomé-Carneiro
- Laboratory of Functional Foods, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, CEI UAM+CSIC, Madrid, 28049, Spain
| | - Luis A Chapado
- Laboratory of Epigenetics of Lipid Metabolism, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, CEI UAM+CSIC, Madrid, 28049, Spain
| | - Alba Macià
- Department of Food Technology, Engineering and Science, XaRTA-TPV, Agrotecnio Center, Escuela Técnica Superior de Ingeniería Agraria, University of Lleida, Lleida, 25198, Spain
| | - Francesco Visioli
- Laboratory of Functional Foods, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, CEI UAM+CSIC, Madrid, 28049, Spain
- Department of Molecular Medicine, University of Padova, Viale G. Colombo 3, Padova, 35121, Italy
| | - Joan C Escola-Gil
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, 08041, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain
- Departament de Bioquímica, Biología Molecular i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193, Spain
| | - Alberto Dávalos
- Laboratory of Epigenetics of Lipid Metabolism, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, CEI UAM+CSIC, Madrid, 28049, Spain
- Consorcio CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII), Madrid, 28029, Spain
| |
Collapse
|
|
10
|
Li H, Seessle J, Staffer S, Tuma-Kellner S, Poschet G, Herrmann T, Chamulitrat W. FATP4 deletion in liver cells induces elevation of extracellular lipids via metabolic channeling towards triglycerides and lipolysis. Biochem Biophys Res Commun 2023; 687:149161. [PMID: 37931418 DOI: 10.1016/j.bbrc.2023.149161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/13/2023] [Accepted: 10/26/2023] [Indexed: 11/08/2023]
Abstract
Evidence from mice with global deletion of fatty-acid transport protein4 (FATP4) indicates its role on β-oxidation and triglycerides (TG) metabolism. We reported that plasma glycerol and free fatty acids (FA) were increased in liver-specific Fatp4 deficient (L-FATP4-/-) mice under dietary stress. We hypothesized that FATP4 may mediate hepatocellular TG lipolysis. Here, we demonstrated that L-FATP4-/- mice showed an increase in these blood lipids, liver TG, and subcutaneous fat weights. We therefore studied TG metabolism in response to oleate treatment in two experimental models using FATP4-knockout HepG2 (HepKO) cells and L-FATP4-/- hepatocytes. Both FATP4-deificient liver cells showed a significant decrease in β-oxidation products by ∼30-35% concomitant with marked upregulation of CD36, FATP2, and FATP5 as well as lipoprotein microsomal-triglyceride-transfer protein genes. By using 13C3D5-glycerol, HepKO cells displayed an increase in metabolically labelled TG species which were further increased with oleate treatment. This increase was concomitant with a step-wise elevation of TG in cells and supernatants as well as the secretion of cholesterol very low-density and high-density lipoproteins. Upon analyzing TG lipolytic enzymes, both mutant liver cells showed marked upregulated expression of hepatic lipase, while that of hormone-sensitive lipase and adipose-triglyceride lipase was downregulated. Lipolysis measured by extracellular glycerol and free FA was indeed increased in mutant cells, and this event was exacerbated by oleate treatment. Taken together, FATP4 deficiency in liver cells led to a metabolic shift from β-oxidation towards lipolysis-directed TG and lipoprotein secretion, which is in line with an association of FATP4 polymorphisms with blood lipids.
Collapse
Affiliation(s)
- Huili Li
- Department of Internal Medicine IV, University Hospital Heidelberg, 69120, Heidelberg, Germany; Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, Hubei, China
| | - Jessica Seessle
- Department of Internal Medicine IV, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Simone Staffer
- Department of Internal Medicine IV, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Sabine Tuma-Kellner
- Department of Internal Medicine IV, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Gernot Poschet
- Metabolomics Core Technology Platform, Centre for Organismal Studies, University of Heidelberg, 69120, Heidelberg, Germany
| | - Thomas Herrmann
- Westkuesten Hospital, Esmarchstraße 50, 25746, Heide, Germany
| | - Walee Chamulitrat
- Department of Internal Medicine IV, University Hospital Heidelberg, 69120, Heidelberg, Germany.
| |
Collapse
|
|
11
|
Göcebe D, Jansakun C, Zhang Y, Staffer S, Tuma-Kellner S, Altamura S, Muckenthaler MU, Merle U, Herrmann T, Chamulitrat W. Myeloid-specific fatty acid transport protein 4 deficiency induces a sex-dimorphic susceptibility for nonalcoholic steatohepatitis in mice fed a high-fat, high-cholesterol diet. Am J Physiol Gastrointest Liver Physiol 2023; 324:G389-G403. [PMID: 36881564 PMCID: PMC10085558 DOI: 10.1152/ajpgi.00181.2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 02/17/2023] [Accepted: 02/26/2023] [Indexed: 03/08/2023]
Abstract
Newborns with FATP4 mutations exhibit ichthyosis prematurity syndrome (IPS), and adult patients show skin hyperkeratosis, allergies, and eosinophilia. We have previously shown that the polarization of macrophages is altered by FATP4 deficiency; however, the role of myeloid FATP4 in the pathogenesis of nonalcoholic steatohepatitis (NASH) is not known. We herein phenotyped myeloid-specific Fatp4-deficient (Fatp4M-/-) mice under chow and high-fat, high-cholesterol (HFHC) diet. Bone-marrow-derived macrophages (BMDMs) from Fatp4M-/- mice showed significant reduction in cellular sphingolipids in males and females, and additionally phospholipids in females. BMDMs and Kupffer cells from Fatp4M-/- mice exhibited increased LPS-dependent activation of proinflammatory cytokines and transcription factors PPARγ, CEBPα, and p-FoxO1. Correspondingly, these mutants under chow diet displayed thrombocytopenia, splenomegaly, and elevated liver enzymes. After HFHC feeding, Fatp4M-/- mice showed increased MCP-1 expression in livers and subcutaneous fat. Plasma MCP-1, IL4, and IL13 levels were elevated in male and female mutants, and female mutants additionally showed elevation of IL5 and IL6. After HFHC feeding, male mutants showed an increase in hepatic steatosis and inflammation, whereas female mutants showed a greater severity in hepatic fibrosis associated with immune cell infiltration. Thus, myeloid-FATP4 deficiency led to steatotic and inflammatory NASH in males and females, respectively. Our work offers some implications for patients with FATP4 mutations and also highlights considerations in the design of sex-targeted therapies for NASH treatment.NEW & NOTEWORTHY FATP4 deficiency in BMDMs and Kupffer cells led to increased proinflammatory response. Fatp4M-/- mice displayed thrombocytopenia, splenomegaly, and elevated liver enzymes. In response to HFHC feeding, male mutants were prone to hepatic steatosis, whereas female mutants showed exaggerated fibrosis. Our study provides insights into a sex-dimorphic susceptibility to NASH by myeloid-FATP4 deficiency.
Collapse
Affiliation(s)
- Deniz Göcebe
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Chutima Jansakun
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
- School of Allied Health Sciences, Walailak University, Nakhonsrithammarat, Thailand
| | - Yuling Zhang
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Simone Staffer
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Sabine Tuma-Kellner
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Sandro Altamura
- Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Martina U Muckenthaler
- Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany
- Translational Lung Research Center Heidelberg, German Center for Lung Research (DZL), German Centre for Cardiovascular Research, Partner Site, University of Heidelberg, Heidelberg, Germany
| | - Uta Merle
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Walee Chamulitrat
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| |
Collapse
|
|
12
|
Shirouchi B, Kawahara Y, Kutsuna Y, Higuchi M, Okumura M, Mitsuta S, Nagao N, Tanaka K. Oral Administration of Chaetoceros gracilis—A Marine Microalga—Alleviates Hepatic Lipid Accumulation in Rats Fed a High-Sucrose and Cholesterol-Containing Diet. Metabolites 2023; 13:metabo13030436. [PMID: 36984876 PMCID: PMC10051878 DOI: 10.3390/metabo13030436] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/11/2023] [Accepted: 03/14/2023] [Indexed: 03/19/2023] Open
Abstract
Microalgae are attracting attention as a next-generation alternative source of protein and essential fatty acids that do not consume large amounts of water or land. Chaetoceros gracilis (C. gracilis)—a marine microalga—is rich in proteins, fucoxanthin, and eicosapentaenoic acid (EPA). Growing evidence indicates that dietary fucoxanthin and EPA have beneficial effects in humans. However, none of these studies have shown that dietary C. gracilis has beneficial effects in mammals. In this study, we investigated the effects of dietary C. gracilis on lipid abnormalities in Sprague-Dawley rats fed a high-sucrose cholesterol-containing diet. Dried C. gracilis was added to the control diet at a final dose of 2 or 5% (w/w). After four weeks, the soleus muscle weights were found to be dose-responsive to C. gracilis and showed a tendency to increase. The hepatic triglyceride and total cholesterol levels were significantly reduced by C. gracilis feeding compared to those in the control group. The activities of FAS and G6PDH, which are related to fatty acid de novo synthesis, were found to be dose-responsive to C. gracilis and tended to decrease. The hepatic glycerol content was also significantly decreased by C. gracilis feeding, and the serum HDL cholesterol levels were significantly increased, whereas the serum levels of cholesterol absorption markers (i.e., campesterol and β-sitosterol) and the hepatic mRNA levels of Scarb1 were significantly decreased. Water-soluble metabolite analysis showed that the muscular contents of several amino acids, including leucine, were significantly increased by C. gracilis feeding. The tendency toward an increase in the weight of the soleus muscle as a result of C. gracilis feeding may be due to the enhancement of muscle protein synthesis centered on leucine. Collectively, these results show that the oral administration of C. gracilis alleviates hepatic lipid accumulation in rats fed a high-sucrose and cholesterol-containing diet, indicating the potential use of C. gracilis as a food resource.
Collapse
Affiliation(s)
- Bungo Shirouchi
- Department of Nutrition Science, Faculty of Nursing and Nutrition, University of Nagasaki, Siebold, 1-1-1 Manabino, Nagayo-cho, Nishi-Sonogi-gun, Nagasaki 851-2195, Japan
- Correspondence: ; Tel.: +81-95-813-5734
| | - Yuri Kawahara
- Department of Nutrition Science, Faculty of Nursing and Nutrition, University of Nagasaki, Siebold, 1-1-1 Manabino, Nagayo-cho, Nishi-Sonogi-gun, Nagasaki 851-2195, Japan
| | - Yuka Kutsuna
- Department of Nutrition Science, Faculty of Nursing and Nutrition, University of Nagasaki, Siebold, 1-1-1 Manabino, Nagayo-cho, Nishi-Sonogi-gun, Nagasaki 851-2195, Japan
| | - Mina Higuchi
- Department of Nutrition Science, Faculty of Nursing and Nutrition, University of Nagasaki, Siebold, 1-1-1 Manabino, Nagayo-cho, Nishi-Sonogi-gun, Nagasaki 851-2195, Japan
| | - Mai Okumura
- Department of Nutrition Science, Faculty of Nursing and Nutrition, University of Nagasaki, Siebold, 1-1-1 Manabino, Nagayo-cho, Nishi-Sonogi-gun, Nagasaki 851-2195, Japan
| | - Sarasa Mitsuta
- Department of Nutrition Science, Faculty of Nursing and Nutrition, University of Nagasaki, Siebold, 1-1-1 Manabino, Nagayo-cho, Nishi-Sonogi-gun, Nagasaki 851-2195, Japan
| | - Norio Nagao
- Blue Scientific Shinkamigoto Co., Ltd., 770 Kogushi, Shin-Kamigoto, Minami-Matsuura, Nagasaki 857-4601, Japan
| | - Kazunari Tanaka
- Regional Partnership Center, University of Nagasaki, Siebold, 1-1-1 Manabino, Nagayo-cho, Nishi-Sonogi-gun, Nagasaki 851-2195, Japan
| |
Collapse
|
|
13
|
Jansakun C, Chunglok W, Altamura S, Muckenthaler M, Staffer S, Tuma-Kellner S, Merle U, Chamulitrat W. Myeloid- and hepatocyte-specific deletion of group VIA calcium-independent phospholipase A2 leads to dichotomous opposing phenotypes during MCD diet-induced NASH. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166590. [PMID: 36334837 DOI: 10.1016/j.bbadis.2022.166590] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/25/2022] [Accepted: 10/25/2022] [Indexed: 11/05/2022]
Abstract
Polymorphisms of phospholipase A2VIA (iPLA2β or PLA2G6) are associated with body weights and blood C-reactive protein. The role of iPLA2β/PLA2G6 in non-alcoholic steatohepatitis (NASH) is still elusive because female iPla2β-null mice showed attenuated hepatic steatosis but exacerbated hepatic fibrosis after feeding with methionine- and choline-deficient diet (MCDD). Herein, female mice with myeloid- (MPla2g6-/-) and hepatocyte- (LPla2g6-/-) specific PLA2G6 deletion were generated and phenotyped after MCDD feeding. Without any effects on hepatic steatosis, MCDD-fed MPla2g6-/- mice showed further exaggeration of liver inflammation and fibrosis as well as elevation of plasma TNFα, CCL2, and circulating monocytes. Bone-marrow-derived macrophages (BMDMs) from MPla2g6-/- mice displayed upregulation of PPARγ and CEBPα proteins, and elevated release of IL6 and CXCL1 under LPS stimulation. LPS-stimulated BMDMs from MCDD-fed MPla2g6-/- mice showed suppressed expression of M1 Tnfa and Il6, but marked upregulation of M2 Arg1, Chil3, IL10, and IL13 as well as chemokine receptors Ccr2 and Ccr5. This in vitro shift was associated with exaggeration of hepatic M1/M2 cytokines, chemokines/chemokine receptors, and fibrosis genes. Contrarily, MCDD-fed LPla2g6-/- mice showed a complete protection which was associated with upregulation of Ppara/PPARα and attenuated expression of Pparg/PPARγ, fatty-acid uptake, triglyceride synthesis, and de novo lipogenesis genes. Interestingly, LPla2g6-/- mice fed with chow or MCDD displayed an attenuation of blood monocytes and elevation of anti-inflammatory lipoxin A4 in plasma and liver. Thus, PLA2G6 inactivation specifically in myeloid cells and hepatocytes led to opposing phenotypes in female mice undergoing NASH. Hepatocyte-specific PLA2G6 inhibitors may be further developed for treatment of this disease.
Collapse
Affiliation(s)
- Chutima Jansakun
- Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80161, Thailand
| | - Warangkana Chunglok
- School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80161, Thailand
| | - Sandro Altamura
- Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany
| | - Martina Muckenthaler
- Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), German Centre for Cardiovascular Research, Partner Site, University of Heidelberg, Germany
| | - Simone Staffer
- Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Sabine Tuma-Kellner
- Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Uta Merle
- Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Walee Chamulitrat
- Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
| |
Collapse
|
|
14
|
Lee SB, Hwang SJ, Son CG. CGX, a standardized herbal syrup, inhibits colon-liver metastasis by regulating the hepatic microenvironments in a splenic injection mouse model. Front Pharmacol 2022; 13:906752. [PMID: 36105183 PMCID: PMC9465806 DOI: 10.3389/fphar.2022.906752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 07/25/2022] [Indexed: 12/03/2022] Open
Abstract
Background: Colon-liver metastasis is observed in approximately 50% of patients with colorectal cancer and is a critical risk factor for a low survival rate. Several clinical studies have reported that colon-liver metastasis is accelerated by pathological hepatic microenvironments such as hepatic steatosis or fibrosis. Chunggan syrup (CGX), a standardized 13-herbal mixture, has been prescribed to patients with chronic liver diseases, including fatty liver, inflammation and fibrotic change, based on preclinical and clinical evidence. Aim of the study: In the present study, we investigated anti-liver metastatic the effects of CGX in a murine colon carcinoma (MC38)-splenic injection mouse model. Materials and methods: C57BL/6N mice were administered with CGX (100, 200 or 400 mg/kg) for 14 days before or after MC38-splenic injection under normal and high-fat diet (HFD) fed conditions. Also, above experiment was repeated without MC38-splenic injection to explore underlying mechanism. Results: The number of tumor nodules and liver weight with tumors were sup-pressed by preadministration of CGX in both normal and HFD fed mice. Regarding its mechanisms, we found that CGX administration significantly activated epithelial-cadherin (E-cadherin), but decreased vascular endothelial-cadherin (VE-cadherin) in hepatic tissues under MC38-free conditions. In addition, CGX administration significantly reduced hepatic steatosis, via modulation of lipolytic and lipogenic molecules, including activated adenosine monophosphate activated protein kinase (AMPK) and peroxisome proliferator activated receptor-alpha (PPARα). Conclusion: The present data indicate that CGX exerts an anti-colon-liver metastatic property via modulation of hepatic lipid related microenvironments.
Collapse
Affiliation(s)
| | | | - Chang-Gue Son
- Institute of Bioscience and Integrative Medicine, Daejeon University, Daejeon, Korea
| |
Collapse
|
|
15
|
Zhang Z, Diao P, Zhang X, Nakajima T, Kimura T, Tanaka N. Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice. Biomedicines 2022; 10:1667. [PMID: 35884970 PMCID: PMC9313206 DOI: 10.3390/biomedicines10071667] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/04/2022] [Accepted: 07/05/2022] [Indexed: 12/12/2022] Open
Abstract
Pemafibrate (PEM) is a novel lipid-lowering drug classified as a selective peroxisome proliferator-activated receptor α (PPARα) modulator whose binding efficiency to PPARα is superior to that of fibrates. This agent is also useful for non-alcoholic fatty liver disease and primary biliary cholangitis with dyslipidemia. The dose of PEM used in some previous mouse experiments is often much higher than the clinical dose in humans; however, the precise mechanism of reduced serum triglyceride (TG) for the clinical dose of PEM has not been fully evaluated. To address this issue, PEM at a clinically relevant dose (0.1 mg/kg/day) or relatively high dose (0.3 mg/kg/day) was administered to male C57BL/6J mice for 14 days. Clinical dose PEM sufficiently lowered circulating TG levels without apparent hepatotoxicity in mice, likely due to hepatic PPARα stimulation and the enhancement of fatty acid uptake and β-oxidation. Interestingly, PPARα was activated only in the liver by PEM and not in other tissues. The clinical dose of PEM also increased serum/hepatic fibroblast growth factor 21 (FGF21) without enhancing hepatic lipid peroxide 4-hydroxynonenal or inflammatory signaling. In conclusion, a clinically relevant dose of PEM in mice efficiently and safely reduced serum TG and increased FGF21 targeting hepatic PPARα. These findings may help explain the multiple beneficial effects of PEM observed in the clinical setting.
Collapse
Affiliation(s)
- Zhe Zhang
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; (Z.Z.); (P.D.); (X.Z.); (T.N.)
| | - Pan Diao
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; (Z.Z.); (P.D.); (X.Z.); (T.N.)
| | - Xuguang Zhang
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; (Z.Z.); (P.D.); (X.Z.); (T.N.)
| | - Takero Nakajima
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; (Z.Z.); (P.D.); (X.Z.); (T.N.)
| | - Takefumi Kimura
- Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan;
| | - Naoki Tanaka
- Department of Global Medical Research Promotion, Shinshu University Graduate School of Medicine, Matsumoto 390-8621, Japan
- International Relations Office, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
- Research Center for Social Systems, Shinshu University, Matsumoto 390-8621, Japan
| |
Collapse
|
|
16
|
Casana E, Jimenez V, Jambrina C, Sacristan V, Muñoz S, Rodo J, Grass I, Garcia M, Mallol C, León X, Casellas A, Sánchez V, Franckhauser S, Ferré T, Marcó S, Bosch F. AAV-mediated BMP7 gene therapy counteracts insulin resistance and obesity. Mol Ther Methods Clin Dev 2022; 25:190-204. [PMID: 35434177 PMCID: PMC8983313 DOI: 10.1016/j.omtm.2022.03.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 03/13/2022] [Indexed: 10/31/2022]
Abstract
Type 2 diabetes, insulin resistance, and obesity are strongly associated and are a major health problem worldwide. Obesity largely results from a sustained imbalance between energy intake and expenditure. Therapeutic approaches targeting metabolic rate may counteract body weight gain and insulin resistance. Bone morphogenic protein 7 (BMP7) has proven to enhance energy expenditure by inducing non-shivering thermogenesis in short-term studies in mice treated with the recombinant protein or adenoviral vectors encoding BMP7. To achieve long-term BMP7 effects, the use of adeno-associated viral (AAV) vectors would provide sustained production of the protein after a single administration. Here, we demonstrated that treatment of high-fat-diet-fed mice and ob/ob mice with liver-directed AAV-BMP7 vectors enabled a long-lasting increase in circulating levels of this factor. This rise in BMP7 concentration induced browning of white adipose tissue (WAT) and activation of brown adipose tissue, which enhanced energy expenditure, and reversed WAT hypertrophy, hepatic steatosis, and WAT and liver inflammation, ultimately resulting in normalization of body weight and insulin resistance. This study highlights the potential of AAV-BMP7-mediated gene therapy for the treatment of insulin resistance, type 2 diabetes, and obesity.
Collapse
Affiliation(s)
- Estefania Casana
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Veronica Jimenez
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Claudia Jambrina
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Victor Sacristan
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
| | - Sergio Muñoz
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Jordi Rodo
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
| | - Ignasi Grass
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
| | - Miquel Garcia
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Cristina Mallol
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
| | - Xavier León
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Alba Casellas
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Víctor Sánchez
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
| | - Sylvie Franckhauser
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Tura Ferré
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Sara Marcó
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Fatima Bosch
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| |
Collapse
|
|
17
|
Consumption of Low Dose Fucoxanthin Does Not Prevent Hepatic and Adipose Inflammation and Fibrosis in Mouse Models of Diet-Induced Obesity. Nutrients 2022; 14:nu14112280. [PMID: 35684079 PMCID: PMC9183127 DOI: 10.3390/nu14112280] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 05/22/2022] [Accepted: 05/25/2022] [Indexed: 11/23/2022] Open
Abstract
Fucoxanthin (FCX) is a xanthophyll carotenoid present in brown seaweed. The goal of this study was to examine whether FCX supplementation could attenuate obesity-associated metabolic abnormalities, fibrosis, and inflammation in two diet-induced obesity (DIO) mouse models. C57BL/6J mice were fed either a high-fat/high-sucrose/high-cholesterol (HFC) diet or a high-fat/high-sucrose (HFS) diet. The former induces more severe liver injury than the latter model. In the first study, male C57BL/6J mice were fed an HFC diet, or an HFC diet containing 0.015% or 0.03% (w/w) FCX powder for 12 weeks to develop obesity-induced nonalcoholic steatohepatitis (NASH). In the second study, mice were fed an HFS diet or an HFS diet containing 0.01% FCX powder for 8 weeks. FCX did not change body weight gain and serum lipid profiles compared to the HFC or HFS controls. No significant differences were present in liver triglyceride and total cholesterol, hepatic fat accumulation, and serum alanine aminotransferase levels between control and FCX-fed mice regardless of whether they were on an HFC or HFS diet. FCX did not mitigate mRNA abundance of genes involved in lipid synthesis, cholesterol metabolism, inflammation, and fibrosis in the liver and white adipose tissue, while hepatic fatty acid β-oxidation genes were significantly elevated by FCX in both HFC and HFS feeding studies. Additionally, in the soleus muscle, FCX supplementation significantly elevated genes that regulate mitochondrial biogenesis and fatty acid β-oxidation, concomitantly increasing mitochondrial DNA copy number, compared with HFC. In summary, FCX supplementation had minor effects on hepatic and white adipose inflammation and fibrosis in two different DIO mouse models.
Collapse
|
|
18
|
Zhang X, Diao P, Yokoyama H, Inoue Y, Tanabe K, Wang X, Hayashi C, Yokoyama T, Zhang Z, Hu X, Nakajima T, Kimura T, Nakayama J, Nakamuta M, Tanaka N. Acidic Activated Charcoal Prevents Obesity and Insulin Resistance in High-Fat Diet-Fed Mice. Front Nutr 2022; 9:852767. [PMID: 35634388 PMCID: PMC9134190 DOI: 10.3389/fnut.2022.852767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 04/11/2022] [Indexed: 11/21/2022] Open
Abstract
Obesity is becoming a major public health problem worldwide. Making charcoal from wood ("Sumi-yaki") has been a traditional activity in the southern part of Nagano Prefecture for centuries, with activated charcoal having reported detoxifying effects. However, it is unclear whether activated charcoal also possesses anti-obesity properties. Additionally, since activated charcoal is usually alkaline and might be affected by gastric juice, we evaluated the effect of acidic activated charcoal on high-fat diet (HFD)-induced obesity. This study demonstrated that co-treatment of acidic activated charcoal with a HFD significantly improved obesity and insulin resistance in mice in a dose-dependent manner. Metabolomic analysis of cecal contents revealed that neutral lipids, cholesterol, and bile acids were excreted at markedly higher levels in feces with charcoal treatment. Moreover, the hepatic expressions of genes encoding cholesterol 7 alpha-hydroxylase and hydroxymethylglutaryl-CoA reductase/synthase 1 were up-regulated by activated charcoal, likely reflecting the enhanced excretions from the intestine and the enterohepatic circulation of cholesterol and bile acids. No damage or abnormalities were detected in the gastrointestinal tract, liver, pancreas, and lung. In conclusion, acidic activated charcoal may be able to attenuate HFD-induced weight gain and insulin resistance without serious adverse effects. These findings indicate a novel function of charcoal to prevent obesity, metabolic syndrome, and related diseases.
Collapse
Affiliation(s)
- Xuguang Zhang
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | - Pan Diao
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | | | | | - Kazuhiro Tanabe
- Medical Solution Promotion Department, Medical Solution Segment, LSI Medience Corporation, Tokyo, Japan
| | - Xiaojing Wang
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Gastroenterology, Lishui Hospital, Zhejiang University School of Medicine, Lishui, China
| | - Chihiro Hayashi
- Medical Solution Promotion Department, Medical Solution Segment, LSI Medience Corporation, Tokyo, Japan
| | | | - Zhe Zhang
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | - Xiao Hu
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China
| | - Takero Nakajima
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takefumi Kimura
- Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Jun Nakayama
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, Fukuoka, Japan
| | - Naoki Tanaka
- Department of Global Medical Research Promotion, Shinshu University Graduate School of Medicine, Matsumoto, Japan
- International Relations Office, Shinshu University School of Medicine, Matsumoto, Japan
- Research Center for Social Systems, Shinshu University, Matsumoto, Japan
| |
Collapse
|
|
19
|
Antihypertensive Effect of Dietary β-Conglycinin in the Spontaneously Hypertensive Rat (SHR). Metabolites 2022; 12:metabo12050422. [PMID: 35629926 PMCID: PMC9146479 DOI: 10.3390/metabo12050422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/30/2022] [Accepted: 05/04/2022] [Indexed: 11/16/2022] Open
Abstract
Dietary β-conglycinin has been shown to increase plasma adiponectin concentration and decrease visceral adipose tissue weight in rats. Since adiponectin is one of the factors regulating blood pressure, as well as modulating lipid metabolism, we examined whether dietary β-conglycinin affects blood pressure in spontaneously hypertensive rats. The experimental diets were prepared according to the AIN-93G formula containing 20% protein, either casein (Control) or casein replaced with soy protein isolate (SOY) or β-conglycinin (β-CON) at the proportion of 50%. Male rats (SHR/Izm, 6 wk-old) were fed the diets for 7 weeks. The SOY compared with the Control significantly suppressed the blood pressure both at week 4 (p = 0.011, Control vs. SOY) and thereafter, and β-CON had even higher suppression (p = 0.0002, Control vs. β-CON). SOY and β-CON increased plasma adiponectin concentration followed by an increase in plasma nitric oxide and possibly a decreasing trend of gene expressions of angiotensinogen in the liver and renin in the kidney. The results indicated suppression by β-conglycinin of increasing blood pressure through an enhancement of plasma adiponectin, probably in combination with a regulation of the renin–angiotensin system in spontaneously hypertensive rats.
Collapse
|
|
20
|
Kim MB, Pham TX, van Luling M, Kostour V, Kang H, Corvino O, Jang H, Odell W, Park YK, Lee JY. Nicotinamide riboside supplementation exerts an anti-obesity effect and prevents inflammation and fibrosis in white adipose tissue of female diet-induced obesity mice. J Nutr Biochem 2022; 107:109058. [PMID: 35643283 DOI: 10.1016/j.jnutbio.2022.109058] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 03/13/2022] [Accepted: 04/17/2022] [Indexed: 12/18/2022]
|
|
21
|
Hamza RZ, Al-Eisa RA, El-Shenawy NS. Possible Ameliorative Effects of the Royal Jelly on Hepatotoxicity and Oxidative Stress Induced by Molybdenum Nanoparticles and/or Cadmium Chloride in Male Rats. BIOLOGY 2022; 11:450. [PMID: 35336823 PMCID: PMC8945475 DOI: 10.3390/biology11030450] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/02/2022] [Accepted: 03/08/2022] [Indexed: 01/24/2023]
Abstract
The present study aimed to investigate the effect of the royal jelly (RJ) on hepatotoxicity induced by molybdenum nanoparticles (MoO3-NPs), cadmium chloride (CdCl2), or their combination in male rats at biochemical, inflammation, immune response, histological, and ultrastructural levels. The physicochemical properties of MoO3-NPs have been characterized, as well as their ultrastructural organization. A rat experimental model was employed to assess the liver toxicity of MoO3-NPs, even in combination with CdCl2. Different cellular studies indicate divergent mechanisms, from increased reactive oxygen species production to antioxidative damage and cytoprotective activity. Seventy male rats were allocated to groups: (i) control; (ii) MoO3-NPs (500 mg/kg); (iii) CdCl2 (6.5 mg/kg); (iv) RJ (85 mg/kg diluted in saline); (v) MoO3-NPs followed by RJ (30 min after the MoO3-NPs dose); (vi) CdCl2 followed by RJ; and (vii) a combination of MoO3-NPs and CdCl2, followed by RJ, for a total of 30 successive days. Hepatic functions, lipid profile, inflammation marker (CRP), antioxidant biomarkers (SOD, CAT, GPx, and MDA), and genotoxicity were examined. Histological changes, an immunological marker for caspase-3, and transmission electron microscope variations in the liver were also investigated to indicate liver status. The results showed that RJ alleviated the hepatotoxicity of MoO3-NPs and/or CdCl2 by improving all hepatic vitality markers. In conclusion, the RJ was more potent and effective as an antioxidant over the oxidative damage induced by the combination of MoO3-NPs and CdCl2.
Collapse
Affiliation(s)
- Reham Z. Hamza
- Zoology Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
- Biology Department, Main Campus, College of Science, Taif University, Taif 21944, Saudi Arabia;
| | - Rasha A. Al-Eisa
- Biology Department, Main Campus, College of Science, Taif University, Taif 21944, Saudi Arabia;
| | - Nahla S. El-Shenawy
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt; or
| |
Collapse
|
|
22
|
Mancina RM, Sasidharan K, Lindblom A, Wei Y, Ciociola E, Jamialahmadi O, Pingitore P, Andréasson AC, Pellegrini G, Baselli G, Männistö V, Pihlajamäki J, Kärjä V, Grimaudo S, Marini I, Maggioni M, Becattini B, Tavaglione F, Dix C, Castaldo M, Klein S, Perelis M, Pattou F, Thuillier D, Raverdy V, Dongiovanni P, Fracanzani AL, Stickel F, Hampe J, Buch S, Luukkonen PK, Prati D, Yki-Järvinen H, Petta S, Xing C, Schafmayer C, Aigner E, Datz C, Lee RG, Valenti L, Lindén D, Romeo S. PSD3 downregulation confers protection against fatty liver disease. Nat Metab 2022; 4:60-75. [PMID: 35102341 PMCID: PMC8803605 DOI: 10.1038/s42255-021-00518-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 12/08/2021] [Indexed: 12/17/2022]
Abstract
Fatty liver disease (FLD) is a growing health issue with burdening unmet clinical needs. FLD has a genetic component but, despite the common variants already identified, there is still a missing heritability component. Using a candidate gene approach, we identify a locus (rs71519934) at the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene resulting in a leucine to threonine substitution at position 186 of the protein (L186T) that reduces susceptibility to the entire spectrum of FLD in individuals at risk. PSD3 downregulation by short interfering RNA reduces intracellular lipid content in primary human hepatocytes cultured in two and three dimensions, and in human and rodent hepatoma cells. Consistent with this, Psd3 downregulation by antisense oligonucleotides in vivo protects against FLD in mice fed a non-alcoholic steatohepatitis-inducing diet. Thus, translating these results to humans, PSD3 downregulation might be a future therapeutic option for treating FLD.
Collapse
Grants
- the MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02364358 (LV), Ricerca Corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico (LV), and the European Union (EU) Programme Horizon 2020 (under grant agreement no. 777377) for the project LITMUS–“Liver Investigation: Testing Marker Utility in Steatohepatitis” (LV).
- Swedish Research Council (Vetenskapsradet (VR), 2021-005208) (SR), the Swedish state under the Agreement between the Swedish government and the county councils (the ALF agreement, SU 2018-04276) (SR), the Swedish Diabetes Foundation (DIA2020-518) (SR), the Swedish Heart Lung Foundation (20200191) (SR), the Wallenberg Academy Fellows from the Knut and Alice Wallenberg Foundation (KAW 2017.0203) (SR), the Novonordisk Project grants in Endocrinology and Metabolism (NNF20OC0063883) (SR), Astra Zeneca Agreement for Research, and Grant SSF ITM17-0384 (SR), Swedish Foundation for Strategic Research (SR)
Collapse
Affiliation(s)
- Rosellina M Mancina
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Kavitha Sasidharan
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Anna Lindblom
- Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Ying Wei
- Ionis Pharmaceuticals, Carlsbad, CA, USA
| | - Ester Ciociola
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Oveis Jamialahmadi
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Piero Pingitore
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Anne-Christine Andréasson
- Bioscience Cardiovascular, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Giovanni Pellegrini
- Pathology, Clinical Pharmacology and Safety Sciences BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Guido Baselli
- Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Ville Männistö
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Clinical Nutrition and Obesity Centre, Kuopio University Hospital, Kuopio, Finland
| | - Vesa Kärjä
- Department of Pathology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Stefania Grimaudo
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Ilaria Marini
- Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Marco Maggioni
- Department of Pathology, Fondazione Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Barbara Becattini
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Federica Tavaglione
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Carly Dix
- Antibody Discovery and Protein Engineering (ADPE), AstraZeneca, Cambridge, UK
| | - Marie Castaldo
- Discovery Biology, Discovery Sciences R&D, AstraZeneca, Gothenburg, Sweden
| | | | | | - Francois Pattou
- University of Lille, Inserm, Lille Pasteur Institute, CHU Lille, European Genomic Institute for Diabetes, U1190 Translational Research in Diabetes, Lille University, Lille, France
- CHU Lille, Department of General and Endocrine Surgery, Intergrated Center for Obesity, Lille, France
| | - Dorothée Thuillier
- University of Lille, Inserm, Lille Pasteur Institute, CHU Lille, European Genomic Institute for Diabetes, U1190 Translational Research in Diabetes, Lille University, Lille, France
| | - Violeta Raverdy
- University of Lille, Inserm, Lille Pasteur Institute, CHU Lille, European Genomic Institute for Diabetes, U1190 Translational Research in Diabetes, Lille University, Lille, France
- CHU Lille, Department of General and Endocrine Surgery, Intergrated Center for Obesity, Lille, France
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Anna Ludovica Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
| | - Jochen Hampe
- Medical Department 1, University Hospital Dresden, Technische Universitaät Dresden (TU Dresden), Dresden, Germany
| | - Stephan Buch
- Medical Department 1, University Hospital Dresden, Technische Universitaät Dresden (TU Dresden), Dresden, Germany
| | - Panu K Luukkonen
- Department of Medicine, University of Helsinki and Helsinki University Central Hosptial, Helsinki, Finland
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
- Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - Daniele Prati
- Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Hannele Yki-Järvinen
- Department of Medicine, University of Helsinki and Helsinki University Central Hosptial, Helsinki, Finland
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Salvatore Petta
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Chao Xing
- McDermott Center for Human Growth and Development University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Clemens Schafmayer
- Department of General, Visceral, Vascular and Transplantation Surgery, University of Rostock, Rostock, Germany
| | - Elmar Aigner
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Christian Datz
- Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, Oberndorf, Austria
| | | | - Luca Valenti
- Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Daniel Lindén
- Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
- Division of Endocrinology, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
- Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
- Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy.
| |
Collapse
|
|
23
|
Wu T, Liu X, Sun Z, Xing S, Han L, Li X, Pan X, Chen J, Zhou M, Derkach T, K. Bielicki J. Fruit of <i>Phyllanthus emblica</i> L. suppresses macrophage foam-cell genesis and vascular lipid deposition using in vivo and <i>in vitro</i> models of early atherosclerosis development. FOOD SCIENCE AND TECHNOLOGY RESEARCH 2022. [DOI: 10.3136/fstr.fstr-d-22-00002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Tao Wu
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences)
| | - Xiaoyu Liu
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences)
| | - Zeyuan Sun
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences)
| | - Shu Xing
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences)
| | - Liwen Han
- School of pharmacy and pharmaceutical sciences, Shandong first medical university ＆ Shandong academy of medical sciences
| | - Xiaobin Li
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences)
| | - Xuefang Pan
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences)
| | - Jianbin Chen
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences)
| | - Mingyang Zhou
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences)
| | | | - John K. Bielicki
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences)
| |
Collapse
|
|
24
|
Zhao Q, Wang Z, Meyers AK, Madenspacher J, Zabalawi M, Zhang Q, Boudyguina E, Hsu FC, McCall CE, Furdui CM, Parks JS, Fessler MB, Zhu X. Hematopoietic Cell-Specific SLC37A2 Deficiency Accelerates Atherosclerosis in LDL Receptor-Deficient Mice. Front Cardiovasc Med 2021; 8:777098. [PMID: 34957260 PMCID: PMC8702732 DOI: 10.3389/fcvm.2021.777098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/16/2021] [Indexed: 11/25/2022] Open
Abstract
Macrophages play a central role in the pathogenesis of atherosclerosis. Our previous study demonstrated that solute carrier family 37 member 2 (SLC37A2), an endoplasmic reticulum-anchored phosphate-linked glucose-6-phosphate transporter, negatively regulates macrophage Toll-like receptor activation by fine-tuning glycolytic reprogramming in vitro. Whether macrophage SLC37A2 impacts in vivo macrophage inflammation and atherosclerosis under hyperlipidemic conditions is unknown. We generated hematopoietic cell-specific SLC37A2 knockout and control mice in C57Bl/6 Ldlr−/− background by bone marrow transplantation. Hematopoietic cell-specific SLC37A2 deletion in Ldlr−/− mice increased plasma lipid concentrations after 12-16 wks of Western diet induction, attenuated macrophage anti-inflammatory responses, and resulted in more atherosclerosis compared to Ldlr−/− mice transplanted with wild type bone marrow. Aortic root intimal area was inversely correlated with plasma IL-10 levels, but not total cholesterol concentrations, suggesting inflammation but not plasma cholesterol was responsible for increased atherosclerosis in bone marrow SLC37A2-deficient mice. Our in vitro study demonstrated that SLC37A2 deficiency impaired IL-4-induced macrophage activation, independently of glycolysis or mitochondrial respiration. Importantly, SLC37A2 deficiency impaired apoptotic cell-induced glycolysis, subsequently attenuating IL-10 production. Our study suggests that SLC37A2 expression is required to support alternative macrophage activation in vitro and in vivo. In vivo disruption of hematopoietic SLC37A2 accelerates atherosclerosis under hyperlipidemic pro-atherogenic conditions.
Collapse
Affiliation(s)
- Qingxia Zhao
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Zhan Wang
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Allison K Meyers
- Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Jennifer Madenspacher
- Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Durham, NC, United States
| | - Manal Zabalawi
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Qianyi Zhang
- Department of Biology, Wake Forest University, Winston-Salem, NC, United States
| | - Elena Boudyguina
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Fang-Chi Hsu
- Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Charles E McCall
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States.,Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Cristina M Furdui
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - John S Parks
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Michael B Fessler
- Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Durham, NC, United States
| | - Xuewei Zhu
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States.,Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, United States
| |
Collapse
|
|
25
|
Kim MB, Lee Y, Bae M, Kang H, Hu S, Pham TX, Lee JY, Park YK. Sugar kelp (Saccharina latissima) inhibits hepatic inflammation and fibrosis in a mouse model of diet-induced nonalcoholic steatohepatitis. J Nutr Biochem 2021; 97:108799. [PMID: 34119629 DOI: 10.1016/j.jnutbio.2021.108799] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 04/18/2021] [Accepted: 05/31/2021] [Indexed: 12/29/2022]
Abstract
Nonalcoholic steatohepatitis (NASH), closely associated with obesity, is a health concern worldwide. We investigated whether the consumption of U.S.-grown sugar kelp (Saccharina latissima), an edible brown alga, can prevent obesity-associated metabolic disturbances and NASH in a mouse model of diet-induced NASH. Male C57BL/6J mice were fed a low-fat diet, a high-fat/high-sucrose/high-cholesterol diet (HF), or a HF diet containing sugar kelp (HF-Kelp) for 14 weeks. HF-Kelp group showed lower body weight with increased O2 consumption, CO2 production, physical activity, and energy expenditure compared with the HF. In the liver, there were significant decreases in weight, triglycerides, total cholesterol, and steatosis with HF-Kelp. The HF-Kelp group decreased hepatic expression of a macrophage marker adhesion G protein-coupled receptor E1 (Adgre1) and an M1 macrophage marker integrin alpha x (Itgax). HF-Kelp group also exhibited decreased liver fibrosis, as evidenced by less expression of fibrogenic genes and collagen accumulation than those of HF group. In epididymal white adipose tissue (eWAT), HF-Kelp group exhibited decreases in eWAT weight and adipocyte size compared with those of the HF. HF-Kelp group showed decreased expression of collagen type VI alpha 1 chain, Adgre1, Itgax, and tumor necrosis factor α in eWAT. We demonstrated, for the first time, that the consumption of U.S-grown sugar kelp prevented the development of obesity and its associated metabolic disturbances, steatosis, inflammation, and fibrosis in the liver and eWAT of a diet-induced NASH mouse model.
Collapse
Affiliation(s)
- Mi-Bo Kim
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Yoojin Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Minkyung Bae
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA; Department of Food and Nutrition, Changwon National University, Changwon, Gyeongsangnam-do, South Korea
| | - Hyunju Kang
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Siqi Hu
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Tho X Pham
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Young-Ki Park
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA.
| |
Collapse
|
|
26
|
Fauste E, Panadero MI, Donis C, Otero P, Bocos C. Pregnancy Is Enough to Provoke Deleterious Effects in Descendants of Fructose-Fed Mothers and Their Fetuses. Nutrients 2021; 13:3667. [PMID: 34684668 PMCID: PMC8539712 DOI: 10.3390/nu13103667] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/14/2021] [Accepted: 10/15/2021] [Indexed: 01/06/2023] Open
Abstract
The role of fructose in the global obesity and metabolic syndrome epidemic is widely recognized. However, its consumption is allowed during pregnancy. We have previously demonstrated that maternal fructose intake in rats induces detrimental effects in fetuses. However, these effects only appeared in adult descendants after a re-exposure to fructose. Pregnancy is a physiological state that leads to profound changes in metabolism and hormone response. Therefore, we wanted to establish if pregnancy in the progeny of fructose-fed mothers was also able to provoke an unhealthy situation. Pregnant rats from fructose-fed mothers (10% w/v) subjected (FF) or not (FC) to a fructose supplementation were studied and compared to pregnant control rats (CC). An OGTT was performed on the 20th day of gestation, and they were sacrificed on the 21st day. Plasma and tissues from mothers and fetuses were analyzed. Although FF mothers showed higher AUC insulin values after OGTT in comparison to FC and CC rats, ISI was lower and leptinemia was higher in FC and FF rats than in the CC group. Accordingly, lipid accretion was observed both in liver and placenta in the FC and FF groups. Interestingly, fetuses from FC and FF mothers also showed the same profile observed in their mothers on lipid accumulation, leptinemia, and ISI. Moreover, hepatic lipid peroxidation was even more augmented in fetuses from FC dams than those of FF mothers. Maternal fructose intake produces in female progeny changes that alter their own pregnancy, leading to deleterious effects in their fetuses.
Collapse
Affiliation(s)
| | | | | | | | - Carlos Bocos
- Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, 28668 Madrid, Spain; (E.F.); (M.I.P.); (C.D.); (P.O.)
| |
Collapse
|
|
27
|
Kang H, Kim MB, Park YK, Lee JY. A mouse model of the regression of alcoholic hepatitis: Monitoring the regression of hepatic steatosis, inflammation, oxidative stress, and NAD + metabolism upon alcohol withdrawal. J Nutr Biochem 2021; 99:108852. [PMID: 34525389 DOI: 10.1016/j.jnutbio.2021.108852] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 06/01/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023]
Abstract
This study aimed to develop a well-characterized mouse model of alcoholic hepatitis (AH) regression. Male C57BL/6J mice were fed a Lieber-DeCarli (LD) control diet or LD containing 5% ethanol for ten days followed by one binge, which is the chronic-binge model of AH developed by the National Institute on Alcohol Abuse and Alcoholism. To determine AH regression, mice previously exposed to ethanol were put on LD control diet and metabolic and inflammatory features were monitored weekly for three weeks. Serum alcohol, total cholesterol, and alanine transaminase levels were increased in ethanol-fed mice, which declined to those of no ethanol controls within one and three weeks after ethanol withdrawal, respectively. Serum malondialdehyde was increased with ethanol feeding, but it was restored to no ethanol control levels within one week. Ethanol-induced changes in the hepatic expression of genes involved in lipogenesis, fatty acid oxidation, ethanol metabolism, and antioxidant response were restored to those of no ethanol controls after 3 weeks of ethanol withdrawal. Also, ethanol-induced hepatic inflammation was gradually decreased during the 3 weeks of ethanol withdrawal. Hepatic nicotinamide adenine dinucleotide (NAD+) levels and the expression of enzymes involved in the NAD+ salvage pathway were decreased by ethanol feeding, which was mitigated after ethanol withdrawal. Ethanol significantly lowered hepatic sirtuin 1 expression, but its levels were restored with ethanol cessation. This study established a mouse model of AH regression, which can be used as a preclinical model to study the potential of dietary bioactives or therapeutic agents on AH regression.
Collapse
Affiliation(s)
- Hyunju Kang
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Mi-Bo Kim
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Young-Ki Park
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA.
| |
Collapse
|
|
28
|
Kang H, Lee Y, Kim MB, Hu S, Jang H, Park YK, Lee JY. The loss of histone deacetylase 4 in macrophages exacerbates hepatic and adipose tissue inflammation in male but not in female mice with diet-induced non-alcoholic steatohepatitis. J Pathol 2021; 255:319-329. [PMID: 34374436 DOI: 10.1002/path.5758] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 06/21/2021] [Accepted: 07/14/2021] [Indexed: 01/02/2023]
Abstract
Epigenetic regulation in macrophages plays a crucial role in the inflammatory response of cells. We investigated the role of macrophage histone deacetylase 4 (HDAC4) in diet-induced obesity and non-alcoholic steatohepatitis using macrophage-specific Hdac4 knockout mice (Hdac4MKO ). Hdac4 floxed control (Hdac4fl/fl ) and Hdac4MKO mice were fed a regular chow diet or an obesogenic high-fat/high-sucrose/high-cholesterol (HF/HS/HC) diet for 12 weeks. The loss of macrophage Hdac4, compared with Hdac4fl/fl control, aggravated the diet-induced inflammation in the liver and white adipose tissue only in male mice. Splenic monocytes isolated from male mice fed the HF/HS/HC diet showed increased lipopolysaccharide (LPS) sensitivity and decreased Ly6C-/Ly6C+ ratios in male Hdac4MKO mice, but not in females. Bone marrow-derived macrophages (BMMs) from male Hdac4MKO mice had a lesser efferocytotic capacity but higher proinflammatory gene expression upon LPS stimulation than male Hdac4fl/fl mice. However, female Hdac4MKO BMMs exhibited the opposite responses. The induction of estrogen receptor α (ERα, Esr1) expression by LPS was less in male but more in female Hdac4MKO BMMs than Hdac4fl/fl BMMs. Moreover, overexpression of human HDAC4 decreased basal expression of Esr1 and abolished its induction by LPS. Inhibition of ERα increased Hdac4 with induction of inflammatory genes, whereas activation of ERα decreased Hdac4 with reduction of inflammatory genes in male and female Hdac4fl/fl BMMs treated with LPS. However, regardless of the inhibition or activation of ERα, proinflammatory genes were induced by LPS more in male Hdac4MKO BMMs than Hdac4fl/fl cells, whereas cells in females showed opposite responses. In conclusion, this study suggests that the lack of macrophage Hdac4 aggravates hepatic and white adipose inflammation in male mice with diet-induced obesity and non-alcoholic steatohepatitis, and not in female mice. HDAC4 and ERα appear to counteract each other, but ERα may not be a major player in sex-dependent inflammatory responses in macrophages deficient in HDAC4. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Hyunju Kang
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Yoojin Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Mi-Bo Kim
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Siqi Hu
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Hyungryun Jang
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Young-Ki Park
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| |
Collapse
|
|
29
|
Aerobic Exercise Training Prevents Insulin Resistance and Hepatic Lipid Accumulation in LDL Receptor Knockout Mice Chronically Fed a Low-Sodium Diet. Nutrients 2021; 13:nu13072174. [PMID: 34202724 PMCID: PMC8308437 DOI: 10.3390/nu13072174] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/11/2021] [Accepted: 06/17/2021] [Indexed: 12/13/2022] Open
Abstract
Background: A low-sodium (LS) diet reduces blood pressure, contributing to the prevention of cardiovascular diseases. However, intense dietary sodium restriction impairs insulin sensitivity and worsens lipid profile. Considering the benefits of aerobic exercise training (AET), the effect of LS diet and AET in hepatic lipid content and gene expression was investigated in LDL receptor knockout (LDLr-KO) mice. Methods: Twelve-week-old male LDLr-KO mice fed a normal sodium (NS) or LS diet were kept sedentary (S) or trained (T) for 90 days. Body mass, plasma lipids, insulin tolerance testing, hepatic triglyceride (TG) content, gene expression, and citrate synthase (CS) activity were determined. Results were compared by 2-way ANOVA and Tukey’s post-test. Results: Compared to NS, LS increased body mass and plasma TG, and impaired insulin sensitivity, which was prevented by AET. The LS-S group, but not the LS-T group, presented greater hepatic TG than the NS-S group. The LS diet increased the expression of genes related to insulin resistance (ApocIII, G6pc, Pck1) and reduced those involved in oxidative capacity (Prkaa1, Prkaa2, Ppara, Lipe) and lipoprotein assembly (Mttp). Conclusion: AET prevented the LS-diet-induced TG accumulation in the liver by improving insulin sensitivity and the expression of insulin-regulated genes and oxidative capacity.
Collapse
|
|
30
|
Amusquivar E, Sánchez-Blanco C, Herrera E. Reduction of litter size during lactation in rats greatly influences fatty acid profiles in dams. J Physiol Biochem 2021; 77:531-538. [PMID: 33909240 DOI: 10.1007/s13105-021-00809-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 03/22/2021] [Indexed: 11/29/2022]
Abstract
This study aimed to determine in lactating rats how fatty acid profiles are affected by litter size. On day 2 after parturition, litters of lactating rats were adjusted to a normal litter size of 9 pups/dam (NL) or to a small litter of 4 pups/dam (SL), and dams were studied at day 21 of lactation. Plasma glucose, insulin, and docosahexaenoic acid (DHA) concentrations were higher in SL than in NL dams, whereas the concentrations of most other fatty acids, triacylglycerols (TAG), and non-esterified fatty acids were lower in the SL dams. In the liver, the concentration of TAG was lower in SL than in NL dams as was the concentration of most fatty acids, with the exception of stearic acid (STA), arachidonic acid (ARA), and DHA concentrations that were higher in SL. Both plasma and liver Δ9 desaturase indices were lower in SL than in NL dams, whereas both Δ5 and Δ6 desaturase indices were higher in SL dams. In the liver, the expression of acetyl CoA carboxylase was lower in SL than in NL dams, and among the different adipose tissue depots, only mesenteric adipose tissue showed a higher concentration of most fatty acids in SL than in NL dams. It is proposed that reduction of litter size during lactation decreases liver lipogenesis de novo, although the synthesis of long-chain polyunsaturated fatty acids from their corresponding precursors increases, and lipolytic activity in mesenteric adipose tissue decreases probably as result of increased insulin responsiveness.
Collapse
Affiliation(s)
| | - Clara Sánchez-Blanco
- Department of Chemistry and Biochemistry, Universidad San Pablo CEU, Madrid, Spain
| | - Emilio Herrera
- Department of Chemistry and Biochemistry, Universidad San Pablo CEU, Madrid, Spain.
| |
Collapse
|
|
31
|
Liu W, Liu J, Xing S, Pan X, Wei S, Zhou M, Li Z, Wang L, Bielicki JK. The benzoate plant metabolite ethyl gallate prevents cellular- and vascular-lipid accumulation in experimental models of atherosclerosis. Biochem Biophys Res Commun 2021; 556:65-71. [PMID: 33839416 DOI: 10.1016/j.bbrc.2021.03.158] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 03/29/2021] [Indexed: 11/18/2022]
Abstract
Ethyl gallate (EG) is a well-known constituent of medicinal plants, but its effects on atherosclerosis development are not clear. In the present study, the anti-atherosclerosis effects of EG and the underlying mechanisms were explored using macrophage cultures, zebrafish and apolipoprotein (apo) E deficient mice. Treatment of macrophages with EG (20 μM) enhanced cellular cholesterol efflux to HDL, and reduced net lipid accumulation in response to oxidized LDL. Secretion of monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) from activated macrophages was also blunted by EG. Fluorescence imaging techniques revealed EG feeding of zebrafish reduced vascular lipid accumulation and inflammatory responses in vivo. Similar results were obtained in apoE-/- mice 6.5 months of age, where plaque lesions and monocyte infiltration into the artery wall were reduced by 70% and 42%, respectively, after just 6 weeks of injections with EG (20 mg/kg). HDL-cholesterol increased 2-fold, serum cholesterol efflux capacity increased by ∼30%, and the levels of MCP-1 and IL-6 were reduced with EG treatment of mice. These results suggest EG impedes early atherosclerosis development by reducing the lipid and macrophage-content of plaque. Underlying mechanisms appeared to involve HDL cholesterol efflux mechanisms and suppression of pro-inflammatory cytokine secretion.
Collapse
Affiliation(s)
- Wenjie Liu
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Jianmin Liu
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Shu Xing
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China.
| | - Xuefang Pan
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Sheng Wei
- Behavioral Phenotyping Core Facility, Shandong University of Traditional Chinese Medicine, Jinan 250353, China.
| | - Mingyang Zhou
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Zifa Li
- Behavioral Phenotyping Core Facility, Shandong University of Traditional Chinese Medicine, Jinan 250353, China
| | - Ling Wang
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - John Kevin Bielicki
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China.
| |
Collapse
|
|
32
|
El-Saad AMA, Abdel-Wahab WM. Naringenin Attenuates Toxicity and Oxidative Stress Induced by Lambda-cyhalothrin in Liver of Male Rats. Pak J Biol Sci 2021; 23:510-517. [PMID: 32363836 DOI: 10.3923/pjbs.2020.510.517] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND AND OBJECTIVES Extensive use of Lambda-cyhalothrin (LTC), a synthetic pyrethroid insecticide, has been associated with serious health problems to the non-target organisms including mammals. The present study investigated the protective effect of naringenin (NGN), an antioxidant flavonoid, against the toxicity induced LTC in the liver of male rats. MATERIALS AND METHODS Five groups of rats were assigned as follows; control group, LTC group (6.12 mg kg-1, 1/10 LD50), LTC-NGN group (6.12 mg kg-1 LTC and 50 mg kg-1 NGN), NGN-LTC group (50 mg kg-1 NGN and 6.12 mg kg-1 LTC) and NGN group (50 mg kg-1). Doses were administrated orally for 21 consecutive days. RESULTS Administration of LTC induced liver damage as indicated by the increase in the activities of aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase and in the level of total bilirubin in serum. LTC also induced a significant elevation in the levels of serum total lipids, total cholesterol, triglycerides and low-density lipoproteins while high-density lipoproteins decreased. Furthermore, LTC significantly disturbed the oxidant/antioxidant balance in the liver as shown by the elevation in lipid peroxidation, lipid hydroperoxides, protein carbonyl content and conjugated dienes with a concomitant inhibition in the major antioxidants such as reduced glutathione and the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase. Both post-treatment and pre-treatment with NGN significantly modulated the LTC-induced hepatotoxicity and oxidative stress in rat's liver and pretreatment was found to be more effective in improving most of the studied parameters in both serum and liver tissue. CONCLUSION NGN could be used as a safe dietary supplement to protect against the toxicity and oxidative stress associated with the use of LTC.
Collapse
|
|
33
|
Efficacy of Mesenchymal Stem Cell and Vitamin D in the Treatment of Diabetes Mellitus Induced in a Rat Model: Pancreatic Tissues. COATINGS 2021. [DOI: 10.3390/coatings11030317] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Treatment with mesenchyme stem cells (MSCs) plays a significant role in the therapies of many diseases such as diabetics. Vitamin D plays a significant role in the development of insulin and can increase the insulin action sensitivity of peripheral tissues. Moreover, there is limited research concerning the mechanism of the therapeutic action of MSCs with the combination of vitamin D (vit. D). Therefore, we evaluated the effect of MSC intervention in a diabetic animal model. Diabetes was induced by streptozotocin (STZ) injection at a dose of 50 mg/kg in adult male rats The diabetic rats were injected with MSCs derived from bone marrow (2 × 106 per rat), either alone or in combination with vit. D through the tail vein for four weeks. Serum insulin, glucose, C-peptide, glycosylated hemoglobin, and lipid profile levels were determined. Pancreatic oxidative stress, histology, and electron microscopy were evaluated, and the gene expression of cytokines was assessed by real-time polymerase chain reaction PCR. MSC treatment suppressed pancreatic inflammatory cytokine secretion and oxidative stress in diabetic rats, resulting in improved pancreatic histology and cellular structure, and the complication of hyperglycemia was observed. Engrafted MSCs were found inside degraded pancreatic regions and regulated inflammatory cytokines. Our results demonstrated that treatment with MSCs and vit. D in combination prevented pancreatic injury via antioxidant and immune regulation in diabetic rats, contributing to the prevention of pancreatic dysfunction, improvement of lipid metabolism, and regulation of cytokine gene expression compared with each one separately. All these mechanisms also improved the histological structure of the pancreas based on transmission electron microscopy. The combination of MSCs and vit. D appears to have contributed to a greater improvement in the diabetic pancreatic complication of rats than was observed by each one separately. Therefore, this association can be used as antidiabetic therapy.
Collapse
|
|
34
|
Refat MS, Hamza RZ, Adam AMA, Saad HA, Gobouri AA, Al-Harbi FS, Al-Salmi FA, Altalhi T, El-Megharbel SM. Quercetin/Zinc complex and stem cells: A new drug therapy to ameliorate glycometabolic control and pulmonary dysfunction in diabetes mellitus: Structural characterization and genetic studies. PLoS One 2021; 16:e0246265. [PMID: 33661932 PMCID: PMC7932096 DOI: 10.1371/journal.pone.0246265] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 01/18/2021] [Indexed: 02/06/2023] Open
Abstract
Medicinal uses and applications of metals and their complexes are of increasing clinical and commercial importance. The ligation behavior of quercetin (Q), which is a flavonoid, and its Zn (II) (Q/Zn) complex were studied and characterized based on elemental analysis, molar conductance, Fourier-transform infrared (FTIR) spectra, electronic spectra, proton nuclear magnetic resonance (1H-NMR), thermogravimetric analysis, and transmission electron microscopy (TEM). FTIR spectral data revealed that Q acts as a bidentate ligand (chelating ligand) through carbonyl C(4) = O oxygen and phenolic C(3)-OH oxygen in conjugation with Zn. Electronic, FTIR, and 1H-NMR spectral data revealed that the Q/Zn complex has a distorted octahedral geometry, with the following chemical formula: [Zn(Q)(NO3)(H2O)2].5H2O. Diabetes was induced by streptozotocin (STZ) injection. A total of 70 male albino rats were divided into seven groups: control, diabetic untreated group and diabetic groups treated with either MSCs and/or Q and/or Q/Zn or their combination. Serum insulin, glucose, C-peptide, glycosylated hemoglobin, lipid profile, and enzymatic and non-enzymatic antioxidant levels were determined. Pancreatic and lung histology and TEM for pancreatic tissues in addition to gene expression of both SOD and CAT in pulmonary tissues were evaluated. MSCs in combination with Q/Zn therapy exhibited potent protective effects against STZ induced hyperglycemia and suppressed oxidative stress, genotoxicity, glycometabolic disturbances, and structural alterations. Engrafted MSCs were found inside pancreatic tissue at the end of the experiment. In conclusion, Q/Zn with MSC therapy produced a synergistic effect against oxidative stress and genotoxicity and can be considered potential ameliorative therapy against diabetes with pulmonary dysfunction, which may benefit against COVID-19.
Collapse
Affiliation(s)
- Moamen S. Refat
- Department of Chemistry, College of Sciences, Taif University, Taif, Saudi Arabia
- Department of Chemistry, Faculty of Science, Port Said University, Port Said, Egypt
| | - Reham Z. Hamza
- Biology Department, Faculty of Science, Taif University, Taif, Saudi Arabia
- Zoology Department, Faculty of Science, Zagazig University, Zagazig, Egypt
| | - Abdel Majid A. Adam
- Department of Chemistry, College of Sciences, Taif University, Taif, Saudi Arabia
| | - Hosam A. Saad
- Department of Chemistry, College of Sciences, Taif University, Taif, Saudi Arabia
- Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
| | - Adil A. Gobouri
- Department of Chemistry, College of Sciences, Taif University, Taif, Saudi Arabia
| | | | | | - Tariq Altalhi
- Department of Chemistry, College of Sciences, Taif University, Taif, Saudi Arabia
| | - Samy M. El-Megharbel
- Department of Chemistry, College of Sciences, Taif University, Taif, Saudi Arabia
- Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
| |
Collapse
|
|
35
|
Gatineau E, Arthur G, Poupeau A, Nichols K, Spear BT, Shelman NR, Graf GA, Temel RE, Yiannikouris FB. The prorenin receptor and its soluble form contribute to lipid homeostasis. Am J Physiol Endocrinol Metab 2021; 320:E609-E618. [PMID: 33459178 PMCID: PMC7988779 DOI: 10.1152/ajpendo.00135.2020] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Obesity is associated with alterations in hepatic lipid metabolism. We previously identified the prorenin receptor (PRR) as a potential contributor to liver steatosis. Therefore, we aimed to determine the relative contribution of PRR and its soluble form, sPRR, to lipid homeostasis. PRR-floxed male mice were treated with an adeno-associated virus with thyroxine-binding globulin promoter-driven Cre to delete PRR in the liver [liver PRR knockout (KO) mice]. Hepatic PRR deletion did not change the body weight but increased liver weights. The deletion of PRR in the liver decreased peroxisome proliferator-activated receptor gamma (PPARγ) and triglyceride levels, but liver PRR KO mice exhibited higher plasma cholesterol levels and lower hepatic low-density lipoprotein receptor (LDLR) and Sortilin 1 (SORT1) proteins than control (CTL) mice. Surprisingly, hepatic PRR deletion elevated hepatic cholesterol, and up-regulated hepatic sterol regulatory element-binding protein 2 (SREBP2) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA-R) genes. In addition, the plasma levels of sPRR were significantly higher in liver PRR KO mice than in controls. In vitro studies in HepG2 cells demonstrated that sPRR treatment upregulated SREBP2, suggesting that sPRR could contribute to hepatic cholesterol biosynthesis. Interestingly, PRR, total cleaved and noncleaved sPRR contents, furin, and Site-1 protease (S1P) were elevated in the adipose tissue of liver PRR KO mice, suggesting that adipose tissue could contribute to the circulating pool of sPRR. Overall, this work supports previous works and opens a new area of investigation concerning the function of sPRR in lipid metabolism and adipose tissue-liver cross talk.NEW & NOTEWORTHY Hepatic PRR and its soluble form, sPRR, contribute to triglyceride and cholesterol homeostasis and hepatic inflammation. Deletion of hepatic PRR decreased triglyceride levels through a PRR-PPARγ-dependent mechanism but increased hepatic cholesterol synthesis through sPRR-medicated upregulation of SREBP-2. Our study highlighted a new paradigm of cross talk between the liver and the adipose tissue involving cholesterol and sPRR.
Collapse
Affiliation(s)
- Eva Gatineau
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
| | - Gertrude Arthur
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
| | - Audrey Poupeau
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
| | - Kellea Nichols
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
| | - Brett T Spear
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
| | - Nathan R Shelman
- Department of Pathology & Laboratory Medicine, University of Kentucky, Lexington, Kentucky
| | - Gregory A Graf
- Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky
| | - Ryan E Temel
- Cardiovascular Research Center and Department of Physiology, University of Kentucky, Lexington, Kentucky
| | | |
Collapse
|
|
36
|
Gil-Zamorano J, Tomé-Carneiro J, Lopez de Las Hazas MC, Del Pozo-Acebo L, Crespo MC, Gómez-Coronado D, Chapado LA, Herrera E, Latasa MJ, Ruiz-Roso MB, Castro-Camarero M, Briand O, Dávalos A. Intestinal miRNAs regulated in response to dietary lipids. Sci Rep 2020; 10:18921. [PMID: 33144601 PMCID: PMC7642330 DOI: 10.1038/s41598-020-75751-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 10/08/2020] [Indexed: 02/07/2023] Open
Abstract
The role of miRNAs in intestinal lipid metabolism is poorly described. The small intestine is constantly exposed to high amounts of dietary lipids, and it is under conditions of stress that the functions of miRNAs become especially pronounced. Approaches consisting in either a chronic exposure to cholesterol and triglyceride rich diets (for several days or weeks) or an acute lipid challenge were employed in the search for intestinal miRNAs with a potential role in lipid metabolism regulation. According to our results, changes in miRNA expression in response to fat ingestion are dependent on factors such as time upon exposure, gender and small intestine section. Classic and recent intestinal in vitro models (i.e. differentiated Caco-2 cells and murine organoids) partially mirror miRNA modulation in response to lipid challenges in vivo. Moreover, intestinal miRNAs might play a role in triglyceride absorption and produce changes in lipid accumulation in intestinal tissues as seen in a generated intestinal Dicer1-deletion murine model. Overall, despite some variability between the different experimental cohorts and in vitro models, results show that some miRNAs analysed here are modulated in response to dietary lipids, hence likely to participate in the regulation of lipid metabolism, and call for further research.
Collapse
Affiliation(s)
- Judit Gil-Zamorano
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM + CSIC, Carretera de Canto Blanco, 8, 28049, Madrid, Spain
| | - João Tomé-Carneiro
- Laboratory of Functional Foods, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM CSIC, 28049, Madrid, Spain
| | - María-Carmen Lopez de Las Hazas
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM + CSIC, Carretera de Canto Blanco, 8, 28049, Madrid, Spain
| | - Lorena Del Pozo-Acebo
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM + CSIC, Carretera de Canto Blanco, 8, 28049, Madrid, Spain
| | - M Carmen Crespo
- Laboratory of Functional Foods, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM CSIC, 28049, Madrid, Spain
| | - Diego Gómez-Coronado
- Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRYCIS, 28034, Madrid, Spain.,Centre of Biomedical Research in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Luis A Chapado
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM + CSIC, Carretera de Canto Blanco, 8, 28049, Madrid, Spain
| | - Emilio Herrera
- Department of Biochemistry and Chemistry, Faculties of Pharmacy and Medicine, Universidad San Pablo CEU, 28668, Madrid, Spain
| | - María-Jesús Latasa
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM + CSIC, Carretera de Canto Blanco, 8, 28049, Madrid, Spain
| | - María Belén Ruiz-Roso
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM + CSIC, Carretera de Canto Blanco, 8, 28049, Madrid, Spain
| | - Mónica Castro-Camarero
- Servicio de Cirugía Experimental, Hospital Universitario Ramón y Cajal, IRYCIS, 28034, Madrid, Spain
| | - Olivier Briand
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, 59000, France
| | - Alberto Dávalos
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM + CSIC, Carretera de Canto Blanco, 8, 28049, Madrid, Spain.
| |
Collapse
|
|
37
|
BMP7 overexpression in adipose tissue induces white adipogenesis and improves insulin sensitivity in ob/ob mice. Int J Obes (Lond) 2020; 45:449-460. [PMID: 33110143 DOI: 10.1038/s41366-020-00700-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 08/26/2020] [Accepted: 10/14/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND/OBJECTIVES During obesity, hypertrophic enlargement of white adipose tissue (WAT) promotes ectopic lipid deposition and development of insulin resistance. In contrast, WAT hyperplasia is associated with preservation of insulin sensitivity. The complex network of factors that regulates white adipogenesis is not fully understood. Bone morphogenic protein 7 (BMP7) can induce brown adipogenesis, but its role on white adipogenesis remains to be elucidated. Here, we assessed BMP7-mediated effects on white adipogenesis in ob/ob mice. METHODS BMP7 was overexpressed in either WAT or liver of ob/ob mice using adeno-associated viral (AAV) vectors. Analysis of gene expression, histological and morphometric alterations, and metabolites and hormones concentrations were carried out. RESULTS Overexpression of BMP7 in adipocytes of subcutaneous and visceral WAT increased fat mass, the proportion of small-size adipocytes and the expression of adipogenic and mature adipocyte genes, suggesting induction of adipogenesis irrespective of fat depot. These changes were associated with reduced hepatic steatosis and improved insulin sensitivity. In contrast, liver-specific overproduction of BMP7 did not promote WAT hyperplasia despite BMP7 circulating levels were similar to those achieved after genetic engineering of WAT. CONCLUSIONS This study unravels a new autocrine/paracrine role of BMP7 on white adipogenesis and highlights that BMP7 may modulate WAT plasticity and increase insulin sensitivity.
Collapse
|
|
38
|
Susilowati R, Jannah J, Maghfuroh Z, Kusuma MT. Antihyperlipidemic effects of apple peel extract in high-fat diet-induced hyperlipidemic rats. J Adv Pharm Technol Res 2020; 11:128-133. [PMID: 33102196 PMCID: PMC7574727 DOI: 10.4103/japtr.japtr_28_20] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 06/06/2020] [Accepted: 06/12/2020] [Indexed: 11/05/2022] Open
Abstract
Hyperlipidemia is generally managed with statin-based drugs. Simvastatin serves as a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitor, with prolonged use proven to cause side effects. In the present study, antihyperlipidemic material is tested for its effect in lowering lipid in animals and its proven ability to bind to HMGR. Hyperlipidemia rats were divided into four groups, with different doses of 0, 57, and 114 mg/kg BW of apple peel extract (APE) and simvastatin (3.6 mg/kg BW). The total cholesterol (TC), total triglyceride (TG), low-density lipoprotein cholesterol (LDLc), and high-density lipoprotein cholesterol (HDLc) serum were measured. In silico inhibition test of HMGR activity was conducted by molecular docking using PyRx software. This process places HMGR as a receptor and active compound of apple peels as a ligand. APE treatment with a dose of 114 mg/kg BW could significantly reduce LDLc and increase serum HDLc levels. Docking tests confirmed that quercetin, chlorogenic acid, epicatechin, and catechins depicted HMGR inhibition. Quercetin could bind to HMGR at a similar location to amino acid residues as simvastatin. These material extracts have inhibited cholesterol synthesis through a stronger HMGR inhibition than simvastatin.
Collapse
Affiliation(s)
- Retno Susilowati
- Department of Biology, Faculty of Science and Technology, State Islamic University of Maulana Malik Ibrahim (UIN), Malang, East Java, Indonesia
| | - Jauharotul Jannah
- Department of Biology, Faculty of Science and Technology, State Islamic University of Maulana Malik Ibrahim (UIN), Malang, East Java, Indonesia
| | - Zahrotul Maghfuroh
- Master Program of Biology, Postgraduate Program, State Islamic University of Maulana Malik Ibrahim (UIN), Malang, East Java, Indonesia
| | - Meike Tiya Kusuma
- Master Program of Biomedical Sciences, Brawijaya University, Malang, East Java, Indonesia
| |
Collapse
|
|
39
|
Naser AM, Rahman M, Unicomb L, Doza S, Selim S, Chaity M, Luby SP, Anand S, Staimez L, Clasen TF, Gujral UP, Gribble MO, Narayan KMV. Past Sodium Intake, Contemporary Sodium Intake, and Cardiometabolic Health in Southwest Coastal Bangladesh. J Am Heart Assoc 2020; 9:e014978. [PMID: 32875927 PMCID: PMC7727005 DOI: 10.1161/jaha.119.014978] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 07/30/2020] [Indexed: 02/07/2023]
Abstract
Background We compared the relationship of past and contemporary sodium (Na) intake with cardiometabolic biomarkers. Methods and Results A total of 1191 participants' data from a randomized controlled trial in coastal Bangladesh were analyzed. Participants provided 24-hour urine Na (24UNa) data for 5 monthly visits. Their fasting blood glucose, total cholesterol, triglycerides, high-density lipoprotein, blood pressure, and 24-hour urine protein were measured at the fifth visit. Participants' mean 24UNa over the first 4 visits was the past Na, and 24UNa of the fifth visit was the contemporary Na intake. We estimated the prevalence ratios of elevated cardiometabolic biomarkers and metabolic syndrome across 24UNa tertiles by multilevel logistic regression using participant-, household-, and community-level random intercepts. Models were adjusted for age, sex, body mass index, smoking, physical activity, alcohol consumption, sleep hours, religion, and household wealth. Compared with participants in tertile 1 of past urine Na, those in tertile 3 had 1.46 (95% CI, 1.08-1.99) times higher prevalence of prediabetes or diabetes mellitus, 5.49 (95% CI, 2.73-11.01) times higher prevalence of large waist circumference, and 1.60 (95% CI, 1.04-2.46) times higher prevalence of metabolic syndrome. Compared with participants in tertile 1 of contemporary urine Na, those in tertile 3 had 1.93 (95% CI, 1.24-3.00) times higher prevalence of prediabetes or diabetes mellitus, 3.14 (95% CI, 1.45-6.83) times higher prevalence of proteinuria, and 2.23 (95% CI, 1.34-3.71) times higher prevalence of large waist circumference. Conclusions Both past and contemporary Na intakes were associated with higher cardiometabolic disease risk.
Collapse
Affiliation(s)
- Abu Mohd Naser
- Emory Global Diabetes Research CenterHubert Department of Global HealthRollins School of Public HealthEmory UniversityAtlantaGA
| | - Mahbubur Rahman
- International Centre for Diarrhoeal Disease ResearchBangladesh (icddr,b)DhakaBangladesh
| | - Leanne Unicomb
- International Centre for Diarrhoeal Disease ResearchBangladesh (icddr,b)DhakaBangladesh
| | - Solaiman Doza
- International Centre for Diarrhoeal Disease ResearchBangladesh (icddr,b)DhakaBangladesh
| | - Shahjada Selim
- Department of EndocrinologyBangabandhu Sheikh Mujib Medical UniversityDhakaBangladesh
| | | | - Stephen P. Luby
- Division of Infectious Diseases and Geographic MedicineStanford UniversityStanfordCA
| | - Shuchi Anand
- Division of NephrologySchool of MedicineStanford UniversityStanfordCA
| | - Lisa Staimez
- Emory Global Diabetes Research CenterHubert Department of Global HealthRollins School of Public HealthEmory UniversityAtlantaGA
| | - Thomas F. Clasen
- Gangarosa Department of Environmental Health SciencesRollins School of Public HealthEmory UniversityAtlantaGA
| | - Unjali P. Gujral
- Emory Global Diabetes Research CenterHubert Department of Global HealthRollins School of Public HealthEmory UniversityAtlantaGA
| | - Matthew O. Gribble
- Gangarosa Department of Environmental Health SciencesRollins School of Public HealthEmory UniversityAtlantaGA
- Department of EpidemiologyRollins School of Public HealthEmory UniversityAtlantaGA
| | - K. M. Venkat Narayan
- Emory Global Diabetes Research CenterHubert Department of Global HealthRollins School of Public HealthEmory UniversityAtlantaGA
| |
Collapse
|
|
40
|
Asai A, Nagao M, Hayakawa K, Miyazawa T, Sugihara H, Oikawa S. Leptin production capacity determines food intake and susceptibility to obesity-induced diabetes in Oikawa-Nagao Diabetes-Prone and Diabetes-Resistant mice. Diabetologia 2020; 63:1836-1846. [PMID: 32561946 DOI: 10.1007/s00125-020-05191-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 04/10/2020] [Indexed: 10/24/2022]
Abstract
AIMS/HYPOTHESIS Obesity caused by overeating plays a pivotal role in the development of type 2 diabetes. However, it remains poorly understood how individual meal size differences are determined before the development of obesity. Here, we investigated the underlying mechanisms in determining spontaneous food intake in newly established Oikawa-Nagao Diabetes-Prone (ON-DP) and Diabetes-Resistant (ON-DR) mice. METHODS Food intake and metabolic phenotypes of ON-DP and ON-DR mice under high-fat-diet feeding were compared from 5 weeks to 10 weeks of age. Differences in leptin status at 5 weeks of age were assessed between the two mouse lines. Adipose tissue explant culture was also performed to evaluate leptin production capacity in vitro. RESULTS ON-DP mice showed spontaneous overfeeding compared with ON-DR mice. Excessive body weight gain and fat accumulation in ON-DP mice were completely suppressed to the levels seen in ON-DR mice by pair-feeding with ON-DR mice. Deterioration of glucose tolerance in ON-DP mice was also ameliorated under the pair-feeding conditions. While no differences were seen in body weight and adipose tissue mass when comparing the two mouse lines at 5 weeks of age, the ON-DP mice had lower plasma leptin concentrations and adipose tissue leptin gene expression levels. In accordance with peripheral leptin status, ON-DP mice displayed lower anorexigenic leptin signalling in the hypothalamic arcuate nucleus when compared with ON-DR mice without apparent leptin resistance. Explant culture studies revealed that ON-DP mice had lower leptin production capacity in adipose tissue. ON-DP mice also displayed higher DNA methylation levels in the leptin gene promoter region of adipocytes when compared with ON-DR mice. CONCLUSIONS/INTERPRETATION The results suggest that heritable lower leptin production capacity plays a critical role in overfeeding-induced obesity and subsequent deterioration of glucose tolerance in ON-DP mice. Leptin production capacity in adipocytes, especially before the development of obesity, may have diagnostic potential for predicting individual risk of obesity caused by overeating and future onset of type 2 diabetes. Graphical abstract.
Collapse
Affiliation(s)
- Akira Asai
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
- Food and Health Science Research Unit, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai, 980-8572, Japan.
| | - Mototsugu Nagao
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Koji Hayakawa
- Department of Toxicology, Faculty of Veterinary Medicine, Okayama University of Science, Imabari, Ehime, Japan
| | - Teruo Miyazawa
- Food and Health Science Research Unit, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai, 980-8572, Japan
| | - Hitoshi Sugihara
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Shinichi Oikawa
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| |
Collapse
|
|
41
|
Im HJ, Hwang SJ, Lee JS, Lee SB, Kang JY, Son CG. Ethyl Acetate Fraction of Amomum xanthioides Ameliorates Nonalcoholic Fatty Liver Disease in a High-Fat Diet Mouse Model. Nutrients 2020; 12:2433. [PMID: 32823613 PMCID: PMC7468949 DOI: 10.3390/nu12082433] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/08/2020] [Accepted: 08/11/2020] [Indexed: 02/06/2023] Open
Abstract
The global prevalence of nonalcoholic fatty liver disease (NAFLD) is estimated to be 25% and has continued to increase; however, no drugs have yet been approved for NAFLD treatments. The ethyl acetate fraction of Amomum xanthioides (EFAX) was previously reported to have an anti-hepatic fibrosis effect, but its effects on steatosis or steatohepatitis remain unclear. This study investigated the anti-fatty liver of EFAX using a high-fat diet mouse model. High-fat diet intake for 8 weeks induced hepatic steatosis with mild inflammation and oxidative damage and increased the adipose tissue weight along with the development of dyslipidemia. EFAX treatment significantly ameliorated the steatohepatic changes, the increased weight of adipose tissues, and the altered serum lipid profiles. These observed effects were possibly due to the lipolysis-dominant activity of EFAX on multiple hepatic proteins including sterol regulatory element-binding protein (mSREBP)-1c, peroxisome proliferator-activated receptor (PPAR)-α, AMP-activated protein kinase, and diglyceride acyltransferases (DGATs). Taken together, these results show that EFAX might be a potential therapeutic agent for regulating a wide spectrum of NAFLDs from steatosis to fibrosis via multiple actions on lipid metabolism-related proteins. Further studies investigating clear mechanisms and their active compounds are needed.
Collapse
Affiliation(s)
| | | | | | | | | | - Chang-Gue Son
- Liver and Immunology Research Center, Dunsan Oriental Hospital of Daejeon University Daedukdae-ro 176 bun-gil 75, Seo-gu, Daejeon 35353, Korea; (H.-J.I.); (S.-J.H.); (J.-S.L.); (S.-B.L.); (J.-Y.K.)
| |
Collapse
|
|
42
|
Kim MB, Lee Y, Bae M, Kang H, Pham TX, Hu S, Lee JY, Park YK. Comprehensive characterization of metabolic, inflammatory and fibrotic changes in a mouse model of diet-derived nonalcoholic steatohepatitis. J Nutr Biochem 2020; 85:108463. [PMID: 32891893 DOI: 10.1016/j.jnutbio.2020.108463] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 05/28/2020] [Accepted: 06/28/2020] [Indexed: 12/11/2022]
Abstract
The objective of this study was to develop a well-characterized mouse model of nonalcoholic steatohepatitis (NASH) with a strong manifestation of liver fibrosis. The progression of metabolic, inflammatory and fibrotic features of this mouse model was monitored by performing in vivo time-course study. Male C57BL/6J mice were fed a high-fat/high-sucrose/high-cholesterol diet (34% fat, 34% sucrose and 2.0% cholesterol, by weight) for 2, 4, 6, 8, 10, 12, 14 or 16 weeks to induce obesity-associated metabolic dysfunctions, inflammation and fibrosis in the liver and white adipose tissue (WAT). Body and liver weights were gradually increased with significant hepatic triglyceride accumulation, i.e., liver steatosis, and marked elevation of serum alanine transaminase levels at week 10. While hepatic inflammation was displayed with the highest expression of macrophage markers and M1 markers at week 6, liver fibrosis determined by collagen accumulation was continuously increased to week 16. In epididymal WAT, weights and adipocyte size peaked at week 6-8. The increased expression of fibrogenic genes preceded inflammatory features (week 2 to 6 vs. week 6 to 16), suggesting that early fibrosis may trigger inflammatory events in the WAT. This study established a mouse model of diet-induced NASH with a strong manifestation of liver fibrosis. This mouse model will be a valuable in vivo tool in studying the pathophysiology of NASH and also in testing preventive and therapeutic potentials of dietary components and drugs against NASH with liver fibrosis.
Collapse
Affiliation(s)
- Mi-Bo Kim
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Yoojin Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Minkyung Bae
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Hyunju Kang
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Tho X Pham
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Siqi Hu
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Young-Ki Park
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA.
| |
Collapse
|
|
43
|
Arab JP, Cabrera D, Sehrawat TS, Jalan-Sakrikar N, Verma VK, Simonetto D, Cao S, Yaqoob U, Leon J, Freire M, Vargas JI, De Assuncao TM, Kwon JH, Guo Y, Kostallari E, Cai Q, Kisseleva T, Oh Y, Arrese M, Huebert RC, Shah VH. Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12. J Hepatol 2020; 73:149-160. [PMID: 32087348 PMCID: PMC7305991 DOI: 10.1016/j.jhep.2020.02.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 01/23/2020] [Accepted: 02/01/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Steatohepatitis drives fibrogenesis in alcohol-related liver disease. Recent studies have suggested that hepatic stellate cells (HSCs) may regulate the parenchymal cell injury and inflammation that precedes liver fibrosis, although the mechanism remains incompletely defined. Neuropilin-1 (NRP-1) and synectin are membrane proteins implicated in HSC activation. In this study, we disrupted NRP-1 and synectin as models to evaluate the role of HSC activation on the development of steatohepatitis in response to alcohol feeding in mice. METHODS Mice with HSC-selective deletion of NRP (ColCre/Nrp1loxP) or synectin (ColCre/synectinloxP) vs. paired Nrp1loxP or synectinloxP mice were fed a control diet or the chronic/binge alcohol feeding model. Several markers of steatosis and inflammation were evaluated. RESULTS ColCre/Nrp1loxP mice showed less fibrosis, as expected, but also less inflammation and steatosis, with lower hepatic triglyceride content. Similar results were observed in the synectin model. Hepatocytes treated with supernatant of HSCs from ColCre/Nrp1loxP mice compared to supernatant from Nrp1loxP mice were protected against ethanol-induced lipid droplet formation. An adipokine and inflammatory protein array from the supernatant of HSCs with NRP-1 knockdown showed a significant reduction in Igfbp3 (a major insulin-like growth factor-binding protein with multiple metabolic functions) and an increase in SerpinA12 (a serine-protease inhibitor) secretion compared to wild-type HSCs. Recombinant Igfbp3 induced lipid droplets, triglyceride accumulation, and lipogenic genes in hepatocytes in vitro, while SerpinA12 was protective against ethanol-induced steatosis. Finally, Igfbp3 was increased, and SerpinA12 was decreased in serum and liver tissue from patients with alcoholic hepatitis. CONCLUSION Selective deletion of NRP-1 from HSCs attenuates alcohol-induced steatohepatitis through regulation of Igfbp3 and SerpinA12 signaling. LAY SUMMARY Hepatic stellate cells are known for their role in fibrosis (scarring of the liver). In this study, we describe their role in the modulation of fat deposition and inflammation in the liver, which occurs secondary to alcohol damage.
Collapse
Affiliation(s)
- Juan P Arab
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA; Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Daniel Cabrera
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile; Departamento de Ciencias Químicas y Biológicas, Universidad Bernardo O Higgins, Santiago, Chile
| | - Tejasav S Sehrawat
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | | | - Vikas K Verma
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Douglas Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Sheng Cao
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Usman Yaqoob
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Jonathan Leon
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Mariela Freire
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Jose I Vargas
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | | | - Jung H Kwon
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Yi Guo
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Qing Cai
- Department of Pathology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California-San Diego, San Diego, CA, USA
| | - Youngman Oh
- Department of Pathology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA
| | - Marco Arrese
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Robert C Huebert
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
| |
Collapse
|
|
44
|
Naser AM, Rahman M, Unicomb L, Parvez SM, Islam S, Doza S, Khan GK, Ahmed KM, Anand S, Luby SP, Shamsudduha M, Gribble MO, Narayan KMV, Clasen TF. Associations of drinking rainwater with macro-mineral intake and cardiometabolic health: a pooled cohort analysis in Bangladesh, 2016-2019. NPJ CLEAN WATER 2020; 3:20. [PMID: 33777415 PMCID: PMC7610435 DOI: 10.1038/s41545-020-0067-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 03/06/2020] [Indexed: 05/19/2023]
Abstract
This study explores the associations of drinking rainwater with mineral intake and cardiometabolic health in the Bangladeshi population. We pooled 10030 person-visit data on drinking water sources, blood pressure (BP) and 24-h urine minerals. Fasting blood glucose (FBG) was measured in 3724 person-visits, and lipids in 1118 person-visits. We measured concentrations of sodium (Na), potassium (K), calcium (Ca) and magnesium (Mg) in 253 rainwater, 935 groundwater and 130 pond water samples. We used multilevel linear or gamma regression models with participant-, household- and community-level random intercepts to estimate the associations of rainwater consumption with urine minerals and cardiometabolic biomarkers. Rainwater samples had the lowest concentrations of Na, K, Ca and Mg. Rainwater drinkers had lower urine minerals than coastal groundwater drinkers: -13.42 (95% CI: -18.27, -8.57) mmol Na/24 h, -2.00 (95% CI: -3.16, -0.85) mmol K/24 h and -0.57 (95% CI: -1.02, -0.16) mmol Mg/24 h. The ratio of median 24-hour urinary Ca for rainwater versus coastal groundwater drinkers was 0.72 (95% CI: 0.64, 0.80). Rainwater drinkers had 2.15 (95% CI: 1.02, 3.27) mm Hg higher systolic BP, 1.82 (95% CI: 1.19, 2.54) mm Hg higher diastolic BP, 0.59 (95% CI: 0.17, 1.01) mmol/L higher FBG and -2.02 (95% CI: -5.85, 0.81) mg/dl change in high-density lipoprotein cholesterol compared with the coastal groundwater drinkers. Drinking rainwater was associated with worse cardiometabolic health measures, which may be due to the lower intake of salubrious Ca, Mg and K.
Collapse
Affiliation(s)
- Abu Mohd Naser
- Emory Global Diabetes Research Center, Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
- Gangarosa Department of Environmental Health Sciences, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Mahbubur Rahman
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), GPO Box 128, Dhaka 1000, Bangladesh
| | - Leanne Unicomb
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), GPO Box 128, Dhaka 1000, Bangladesh
| | - Sarker Masud Parvez
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), GPO Box 128, Dhaka 1000, Bangladesh
| | - Shariful Islam
- Department of Agricultural Chemistry, Patuakhali Science and Technology University, Dumki, Patuakhali 8602, Bangladesh
| | - Solaiman Doza
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), GPO Box 128, Dhaka 1000, Bangladesh
| | - Golam Kibria Khan
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), GPO Box 128, Dhaka 1000, Bangladesh
| | | | - Shuchi Anand
- Division of Nephrology, School of Medicine, Stanford University, Stanford, CA, USA
| | - Stephen P Luby
- Woods Institute for the Environment, Stanford University, Stanford, CA, USA
| | - Mohammad Shamsudduha
- Institute for Risk and Disaster Reduction, University College London, London, UK
- Department of Geography, University of Sussex, Brighton, UK
| | - Matthew O Gribble
- Gangarosa Department of Environmental Health Sciences, Rollins School of Public Health, Emory University, Atlanta, GA, USA
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - K M Venkat Narayan
- Emory Global Diabetes Research Center, Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Thomas F Clasen
- Gangarosa Department of Environmental Health Sciences, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| |
Collapse
|
|
45
|
AlBasher G, Abdel-Daim MM, Almeer R, Ibrahim KA, Hamza RZ, Bungau S, Aleya L. Synergistic antioxidant effects of resveratrol and curcumin against fipronil-triggered oxidative damage in male albino rats. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2020; 27:6505-6514. [PMID: 31873888 DOI: 10.1007/s11356-019-07344-8] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 12/09/2019] [Indexed: 02/07/2023]
Abstract
Fipronil (FPN), a phenylpyrazole insecticide, has been receiving increased attention owing to its toxicity, which is largely mediated through its effects on antioxidant systems. The present study was undertaken to assess the effects of resveratrol (RSV) and curcumin (CUR) on oxidative damage induced by FPN. Forty mature male Wistar rats were randomized into five groups (n = 8 per group): the first group was the control; the second was administered FPN (10 mg/kg); and the third, fourth, and fifth were co-treated with RSV (10 mg/kg), CUR (200 mg/kg), and their combination, respectively, 2 h prior to FPN administration. All animals were dosed via oral gavage for 4 weeks. FPN significantly (p < 0.05) elevated the sera of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-glutamyl transferase (GGT), urea, creatinine, and cholesterol levels, whereas serum total protein, albumin, and triglyceride levels were significantly (p < 0.05) decreased, compared to those of the control group. Reduced glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were decreased (p < 0.05) in the FPN-treated group compared to those in the control group; however, malondialdehyde (MDA) and nitric oxide (NO) levels were markedly increased (p < 0.05) in the hepatic, renal, and brain tissues. Co-treatment with RSV or CUR alleviated (p ˂ 0.05) the increased lipid peroxidation and changes in enzymatic/nonenzymatic antioxidants induced by FPN; all these variables mostly returned to normal levels with the combined of RSV and CUR treatment. In conclusion, RSV and/or CUR relieved and synergistically reversed the FPN-induced tissue oxidative injury, probably by improving the antioxidant defenses via their free radical scavenging and antioxidant characteristics.
Collapse
Affiliation(s)
- Gadah AlBasher
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
| | - Mohamed M Abdel-Daim
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia.
- Department of Pharmacology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, 41522, Egypt.
| | - Rafa Almeer
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
| | - Khairy A Ibrahim
- Mammalian Toxicology Department, Central Agricultural Pesticides Laboratory, Agricultural Research Center, Dokki, Giza, 12618, Egypt
| | - Reham Z Hamza
- Zoology Department, Faculty of Science, Zagazig University, Zagazig, 44519, Egypt
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
| | - Lotfi Aleya
- Chrono-Environnement Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, F-25030, Besançon Cedex, France
| |
Collapse
|
|
46
|
Oluba OM. Erythrocyte Lipid and Antioxidant Changes in <i>Plasmodium falciparum</i>-infected Children Attending Mother and Child Hospital in Akure, Nigeria. Pak J Biol Sci 2020; 22:257-264. [PMID: 31930848 DOI: 10.3923/pjbs.2019.257.264] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND AND OBJECTIVE Understanding the molecular and cellular pathways activated in response to Plasmodium falciparum infection is crucial for the development of pharmacological intervention to malaria. The present study was designed to evaluate the lipid components and the oxidative status of erythrocyte obtained from children under 5 years infected with Plasmodium falciparum. MATERIALS AND METHODS Parasitemia was assessed prior and after treatment with antimalarial, erythrocyte lipid profile, levels of lipid peroxidation and antioxidant status (reduced glutathione, GSH; superoxide dismutase, SOD; catalase and glutathione peroxidase, GPx) were measured. RESULTS Results obtained showed that in Plasmodium infected erythrocyte, the total phospholipids, cholesterol and LDL-cholesterol concentrations were significantly elevated beyond the normal level. In addition, an upsurge in erythrocyte oxidant (lipid peroxide) status with a concomitant downregulation of the antioxidant status (GSH concentration and SOD, catalase and GPx activities) was observed in P. falciparum-infected children. However, following a three-day treatment with artemisinin combination drugs, there was a significant reduction in erythrocyte phospholipids, total cholesterol and LDL-cholesterol concentration as well as lipid peroxide levels. Significant augmentation in erythrocyte antioxidant status (GSH, SOD, catalase and GPx) were also observed after treatment with antimalarials. CONCLUSION This study demonstrated that erythrocyte lipids and oxidative status are usually altered in Plasmodium falciparum-infected children. Thus, monitoring erythrocyte lipid profile and oxidative status could offer a viable diagnostic strategy in early detection of malaria in children.
Collapse
|
|
47
|
Minniti ME, Ahmed O, Pedrelli M. Enzymatic Quantification of Liver Lipids After Folch Extraction. Methods Mol Biol 2020; 2164:101-108. [PMID: 32607887 DOI: 10.1007/978-1-0716-0704-6_11] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The determination of the lipid content in liver offers the potential to investigate metabolic alterations in different research contexts. Here, we describe a method to determine cholesterol, triglycerides, and phospholipids in liver samples based on total lipid isolation by a 2:1 chloroform-methanol mixture (Folch extraction) and specific enzymatic colorimetric microassays in plate.
Collapse
Affiliation(s)
- Mirko E Minniti
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
| | - Osman Ahmed
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Matteo Pedrelli
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
| |
Collapse
|
|
48
|
Karim N, Rahman MA, Changlek S, Tangpong J. Short-Time Administration of Xanthone From Garcinia mangostana Fruit Pericarp Attenuates the Hepatotoxicity and Renotoxicity of Type II Diabetes Mice. J Am Coll Nutr 2019; 39:501-510. [PMID: 31846399 DOI: 10.1080/07315724.2019.1696251] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Objective: Our previous studies reported that xanthone can protect from hyperglycemia-induced diabetes mellitus (DM) via possessing antioxidant activity. An attempt has been made to evaluate the protective effect of xanthone against hepatotoxicity and renotoxicity of high-fat-diet and single-dose-streptozotocin-induced DM mice.Method: In this research, in vitro antioxidant and antidiabetic assays were performed. In vivo oral glucose and maltose tolerance test, metabolic parameters, plasma biochemical markers, oxidative status, etc. were evaluated in experimental mice. In addition, liver/kidney tissue histology and kidney apoptosis were observed using hematoxylin and eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, respectively.Results: Xanthone exhibited potent in vitro antioxidant and antidiabetic activity. Xanthone treatments to diabetic mice significantly (p < 0.05) improved the biochemical and antioxidant parameters compared to that of the control group. Moreover, xanthone treatments also significantly (p < 0.05) reformed the liver and kidney histological alterations as well as reduced the cellular apoptosis of kidney tissue.Conclusions: All findings together concluded that xanthone could be a dietary supplement for the patient with diabetic complications.
Collapse
Affiliation(s)
- Naymul Karim
- Biomedical Sciences, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat, Thailand
| | - Md Atiar Rahman
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong, Bangladesh
| | - Suksan Changlek
- Biomedical Sciences, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat, Thailand.,Research Excellence Center for Innovation and Health Products (RECIHP), Walailak University, Nakhon Si Thammarat, Thailand
| | - Jitbanjong Tangpong
- Biomedical Sciences, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat, Thailand.,Research Excellence Center for Innovation and Health Products (RECIHP), Walailak University, Nakhon Si Thammarat, Thailand
| |
Collapse
|
|
49
|
Lee SB, Kim HG, Lee JS, Kim WY, Lee MM, Kim YH, Lee JO, Kim HS, Son CG. Intermittent restraint-induced sympathetic activation attenuates hepatic steatosis and inflammation in a high-fat diet-fed mouse model. Am J Physiol Gastrointest Liver Physiol 2019; 317:G811-G823. [PMID: 31604029 DOI: 10.1152/ajpgi.00047.2019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is very prevalent worldwide and is associated with insulin resistance and metabolic syndrome. Stress is a physiological and biological response to maintain homeostasis of the body against stressors while severe stress response is an important contributor to various illnesses, including metabolic syndrome and brain disorders. We have evaluated the effects of intermittent restraint stress on NAFLD in a high-fat diet (HFD)-fed mouse model. C57/BL6 mice had free access to a 60% HFD for 8 wk, with or without intermittent restraint stress (3 h) conducted three times a week. HFD administration increased fat accumulation in liver tissues. Unlike the stressed standard diet group, the levels of hepatic total cholesterol and triglycerides were significantly ameliorated in the HFD with stress group compared with the HFD alone group. These beneficial results were in accordance with serum levels of liver enzymes (aspartate transaminase, alanine transaminase) and hepatic levels of TNF-α and oxidative stress parameters (reactive oxygen species, nitric oxide, and malondialdehyde). The intermittent restraint stress significantly attenuated the HFD-derived alterations in serum insulin levels, hepatic protein kinase B activity, and gene expression, especially related to lipogenesis. This intermittent restraint stress also elevated the serum epinephrine concentration and activated the adrenergic receptor β2 or β3 in livers or white adipose tissue (WAT). Activation of energy expenditure markers (uncoupling protein 1, peroxisome proliferator-activated receptor-γ coactivator-1α) in brown adipose tissue and the browning of WAT were also observed in the HFD with stress group. Taken together, our findings showed the beneficial effects of sympathetic activation by intermittent restraint stress on HFD-induced hepatic steatosis and partial inflammation.NEW & NOTEWORTHY In modern society, stress is a part of daily life, and a certain level of stress is inevitable to most of the general population. Uncontrolled severe stress is obviously harmful; however, certain kind/level of stress could be beneficial on lipid metabolism via sympathetic activation. Our data suggest that a sympathetic activation by intermittent restraint stress could play a positive role in maintaining the balance of hepatic lipid metabolism, especially under high-fat diet conditions.
Collapse
Affiliation(s)
- Sung Bae Lee
- Institute of Traditional Medicine and Bioscience, Daejeon University, Daejeon, Korea
| | - Hyeong Geug Kim
- Institute of Traditional Medicine and Bioscience, Daejeon University, Daejeon, Korea
| | - Jin Seok Lee
- Institute of Traditional Medicine and Bioscience, Daejeon University, Daejeon, Korea
| | - Won Yong Kim
- Institute of Traditional Medicine and Bioscience, Daejeon University, Daejeon, Korea
| | - Myong Min Lee
- Institute of Traditional Medicine and Bioscience, Daejeon University, Daejeon, Korea
| | - Yun Hee Kim
- Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
| | - Jung Ok Lee
- Department of Anatomy, Korea University College of Medicine, Seoul, Korea
| | - Hyeon Soo Kim
- Department of Anatomy, Korea University College of Medicine, Seoul, Korea
| | - Chang Gue Son
- Institute of Traditional Medicine and Bioscience, Daejeon University, Daejeon, Korea
| |
Collapse
|
|
50
|
Lee SA, Jiang H, Feranil JB, Brun PJ, Blaner WS. Adipocyte-specific expression of a retinoic acid receptor α dominant negative form causes glucose intolerance and hepatic steatosis in mice. Biochem Biophys Res Commun 2019; 514:1231-1237. [PMID: 31109648 DOI: 10.1016/j.bbrc.2019.05.075] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 05/09/2019] [Indexed: 11/30/2022]
Abstract
All-trans-retinoic acid (ATRA) has been well described as a positive regulator for early stage of adipocyte differentiation and lipid metabolism and also linked to an in vivo fat-lowering effect in mice. However, not all studies support this association. Our objective was to characterize the action of ATRA in mature adipocytes of mice by ablating RAR signaling through overexpression of a well-characterized dominant negative RARα mutant (RARdn) form specifically in adipocytes. Altered RAR signaling in adipocytes resulted in a significant decrease in ATRA levels in visceral and brown adipose tissues as well as liver tissue. This was linked to significant impairments in glucose clearance and elevated hepatic lipid accumulation for chow diet fed mice, indicating the development of metabolic disease, including hepatic steatosis. In addition, we found that adipose RARdn expression in mice fed a chow diet decreased thermogenesis. We conclude that altered RAR signaling and ATRA levels in adipocytes impacts glucose and lipid metabolism in mice.
Collapse
Affiliation(s)
- Seung-Ah Lee
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, United States; Present Address: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
| | - Hongfeng Jiang
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, United States.
| | - Jun B Feranil
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, United States.
| | - Pierre-Jacques Brun
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, United States.
| | - William S Blaner
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, United States.
| |
Collapse
|