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Lu J, Shataer D, Yan H, Dong X, Zhang M, Qin Y, Cui J, Wang L. Probiotics and Non-Alcoholic Fatty Liver Disease: Unveiling the Mechanisms of Lactobacillus plantarum and Bifidobacterium bifidum in Modulating Lipid Metabolism, Inflammation, and Intestinal Barrier Integrity. Foods 2024; 13:2992. [PMID: 39335920 PMCID: PMC11431124 DOI: 10.3390/foods13182992] [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: 07/27/2024] [Revised: 09/12/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
In recent years, the prevalence of non-alcoholic fatty liver disease (NAFLD) has risen annually, yet due to the intricacies of its pathogenesis and therapeutic challenges, there remains no definitive medication for this condition. This review explores the intricate relationship between the intestinal microbiome and the pathogenesis of NAFLD, emphasizing the substantial roles played by Lactobacillus plantarum and Bifidobacterium bifidum. These probiotics manipulate lipid synthesis genes and phosphorylated proteins through pathways such as the AMPK/Nrf2, LPS-TLR4-NF-κB, AMPKα/PGC-1α, SREBP-1/FAS, and SREBP-1/ACC signaling pathways to reduce hepatic lipid accumulation and oxidative stress, key components of NAFLD progression. By modifying the intestinal microbial composition and abundance, they combat the overgrowth of harmful bacteria, alleviating the inflammatory response precipitated by dysbiosis and bolstering the intestinal mucosal barrier. Furthermore, they participate in cellular immune regulation, including CD4+ T cells and Treg cells, to suppress systemic inflammation. L. plantarum and B. bifidum also modulate lipid metabolism and immune reactions by adjusting gut metabolites, including propionic and butyric acids, which inhibit liver inflammation and fat deposition. The capacity of probiotics to modulate lipid metabolism, immune responses, and gut microbiota presents an innovative therapeutic strategy. With a global increase in NAFLD prevalence, these insights propose a promising natural method to decelerate disease progression, avert liver damage, and tackle associated metabolic issues, significantly advancing microbiome-focused treatments for NAFLD.
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Affiliation(s)
- Jing Lu
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China; (J.L.); (D.S.); (H.Y.); (M.Z.); (Y.Q.)
| | - Dilireba Shataer
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China; (J.L.); (D.S.); (H.Y.); (M.Z.); (Y.Q.)
| | - Huizhen Yan
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China; (J.L.); (D.S.); (H.Y.); (M.Z.); (Y.Q.)
| | - Xiaoxiao Dong
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China; (J.L.); (D.S.); (H.Y.); (M.Z.); (Y.Q.)
| | - Minwei Zhang
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China; (J.L.); (D.S.); (H.Y.); (M.Z.); (Y.Q.)
| | - Yanan Qin
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China; (J.L.); (D.S.); (H.Y.); (M.Z.); (Y.Q.)
| | - Jie Cui
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing 211816, China
| | - Liang Wang
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China; (J.L.); (D.S.); (H.Y.); (M.Z.); (Y.Q.)
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Olatunji LA, Badmus OO, Abdullahi KO, Usman TO, ologe M, Adejare A. Depletion of hepatic glutathione and adenosine by glucocorticoid exposure in Wistar rats is pregnancy-independent. Toxicol Rep 2024; 12:485-491. [PMID: 38741615 PMCID: PMC11090063 DOI: 10.1016/j.toxrep.2024.04.011] [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: 06/03/2023] [Revised: 02/24/2024] [Accepted: 04/29/2024] [Indexed: 05/16/2024] Open
Abstract
Liver diseases have gained increasing attention due to their substantial impact on health, independently as well as in association with cardio-metabolic disorders. Studies have suggested that glutathione and adenosine assist in providing protection against oxidative stress and inflammation while glucocorticoid (GC) therapy has been associated with chronic inflammatory disorders, even in pregnancy. The implications of Glucocorticoid exposure on maternal health and fetal growth is a concern, however, the possible role of glutathione and adenosine has not been thoroughly investigated. The study therefore hypothesize that exposure to glucocorticoids leads to depletion of hepatic glutathione and adenosine levels, contributing to oxidative stress and tissue injury. Additionally, we aim to investigate whether the effects of glucocorticoids on hepatic health are pregnancy dependent in female rats. Twelve Pregnant and twelve age-matched non-pregnant rats were used for this study; an exogenous administration of glucocorticoid (Dex: 0.2 mg/kg) or vehicle (po) was administered to six pregnant and six non-pregnant rats from gestational day 14 to 19 or for a period of 6 days respectively. Data obtained showed that GC exposure led to a decrease in hepatic glucose-6-phosphate dehydrogenase, glutathione peroxidase, GSH/GSSG ratio and adenosine content in both pregnant and non-pregnant rats. In addition, increased activities of adenosine deaminase and xanthine oxidase, along with increased production of uric acid and increased levels of lactate dehydrogenase, aspartate aminotransferase, alanine transferase, alkaline phosphatase and gamma-glutamyl transferase were observed. In summary, the study indicates that GC-induced liver damage is underlined by depleted hepatic adenosine and glutathione levels as well as elevated markers of tissue inflammation and/or injury. Furthermore, the findings suggest that the effects of GC exposure on hepatic health are pregnancy independent.
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Affiliation(s)
- Lawrence A. Olatunji
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Olufunto O. Badmus
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
- Department of Physiology and Biophysics, Cardiorenal, and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Kamaldeen O. Abdullahi
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Taofeek O. Usman
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburg, PA, USA
| | - Mary ologe
- Department of Pharmacology and Therapeutics, University of Ilorin, Ilorin, Nigeria
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Rainu SK, Singh N. 3D microscaffolds with triple-marker sensitive nanoprobes for studying fatty liver disease in vitro. NANOSCALE 2024; 16:10048-10063. [PMID: 38712552 DOI: 10.1039/d4nr00434e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a heterogeneous condition that encompasses a wide range of liver diseases that progresses from simple hepatic steatosis to the life-threatening state of cirrhosis. However, due to the heterogeneity of this disease, comprehensive analysis of several physicochemical and biological factors that drive its progression is necessary. Therefore, an in vitro platform is required that would enable real-time monitoring of these changes to better understand the progression of these diseases. The earliest stage of NAFLD, i.e. hepatic steatosis, is characterised by triglyceride accumulation in the form of lipid vacuoles in the cytosol of hepatocytes. This fatty acid accumulation is usually accompanied by hepatic inflammation, leading to tissue acidification and dysregulated expression of certain proteases such as matrix metalloproteinases (MMPs). Taking cues from the biological parameters of the disease, we report here a 3D in vitro GelMA/alginate microscaffold platform encapsulating a triple-marker (pH, MMP-3 and MMP-9) sensitive fluorescent nanoprobe for monitoring, and hence, distinguishing the fatty liver disease (hepatic steatosis) from healthy livers on the basis of pH change and MMP expression. The nanoprobe consists of a carbon nanoparticle (CNP) core, which exhibits intrinsic pH-dependent fluorescence properties, decorated either with an MMP-3 (NpMMP3) or MMP-9 (NpMMP9) sensitive peptide substrate. These peptide substrates are flanked with a fluorophore-quencher pair that separates on enzymatic cleavage, resulting in fluorescence emission. The cocktail of these nanoprobes generated multiple fluorescence signals corresponding to slightly acidic pH (blue) and overexpression of MMP-3 (green) and MMP-9 (red) enzymes in a 3D in vitro fatty liver model, whereas no/negligible fluorescence signals were observed in a healthy liver model. Moreover, this platform enabled us to mimic fatty liver disease in a more realistic manner. Therefore, this 3D in vitro platform encapsulating triple-marker sensitive fluorescent nanoprobes would facilitate the monitoring of the changes in pH and MMP expression, thereby enabling us to distinguish a healthy liver from a diseased liver and to study liver disease stages on the basis of these markers.
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Affiliation(s)
- Simran Kaur Rainu
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
| | - Neetu Singh
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
- Biomedical Engineering Unit, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
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Alghamdi W, Mosli M, Alqahtani SA. Gut microbiota in MAFLD: therapeutic and diagnostic implications. Ther Adv Endocrinol Metab 2024; 15:20420188241242937. [PMID: 38628492 PMCID: PMC11020731 DOI: 10.1177/20420188241242937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 02/22/2024] [Indexed: 04/19/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease, is becoming a significant contributor to chronic liver disease globally, surpassing other etiologies, such as viral hepatitis. Prevention and early treatment strategies to curb its growing prevalence are urgently required. Recent evidence suggests that targeting the gut microbiota may help treat and alleviate disease progression in patients with MAFLD. This review aims to explore the complex relationship between MAFLD and the gut microbiota in relation to disease pathogenesis. Additionally, it delves into the therapeutic strategies targeting the gut microbiota, such as diet, exercise, antibiotics, probiotics, synbiotics, glucagon-like peptide-1 receptor agonists, and fecal microbiota transplantation, and discusses novel biomarkers, such as microbiota-derived testing and liquid biopsy, for their diagnostic and staging potential. Overall, the review emphasizes the urgent need for preventive and therapeutic strategies to address the devastating consequences of MAFLD at both individual and societal levels and recognizes that further exploration of the gut microbiota may open avenues for managing MAFLD effectively in the future.
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Affiliation(s)
- Waleed Alghamdi
- Division of Gastroenterology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mahmoud Mosli
- Division of Gastroenterology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Saleh A. Alqahtani
- Organ Transplant Center of Excellence, King Faisal Specialist Hospital & Research Center, Riyadh 11211, Saudi Arabia
- Division of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
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Lu Y, Pike JR, Hoogeveen R, Walker K, Raffield L, Selvin E, Avery C, Engel S, Mielke MM, Garcia T, Heiss G, Palta P. Nonalcoholic Fatty Liver Disease and Longitudinal Change in Imaging and Plasma Biomarkers of Alzheimer Disease and Vascular Pathology. Neurology 2024; 102:e209203. [PMID: 38471046 PMCID: PMC11033987 DOI: 10.1212/wnl.0000000000209203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 01/23/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Prospective measures of plasma and cerebral MRI biomarkers of Alzheimer disease (AD) and vascular neuropathology provide an opportunity to investigate possible mechanisms linking liver disease and dementia. We aimed to quantify the association of midlife nonalcoholic fatty liver disease (NAFLD) with change in plasma and brain MRI biomarkers of AD and vascular neuropathology. METHODS We included participants from the Atherosclerosis Risk in Communities Study with brain MRI measurements of white matter hyperintensity (WMH) volume and temporal-parietal lobe cortical thickness meta region of interest (ROI) at up to 2 different visits, in 2011-13 and 2016-19, and plasma biomarkers of β-amyloid (Aβ)42:40, phosphorylated tau at threonine 181, and neurofilament light (NfL) were measured up to 3 times in 1993-95, 2011-13, and 2016-19. NAFLD was categorized using the fatty liver index in 1990-92. Multivariate linear regression was performed for associations between midlife NAFLD and change in plasma and brain MRI biomarkers of AD and vascular neuropathology. The primary models adjusted for demographics, Apolipoprotein E, alcohol use, and kidney function. RESULTS Among 1,706 participants (mean age 56 years, 62% female, 28% Black), midlife NAFLD vs no NAFLD was associated with greater late-life WMH volume (difference per SD 0.19, 95% CI 0.06-0.31) and faster late-life WMH increase over 6 years (difference in annual change, SD 0.28, 95% CI 0.05-0.51), suggesting accumulating vascular pathology. Midlife NAFLD vs no NAFLD was also associated with AD biomarkers in midlife (lower Aβ42:40 [SD -0.21, 95% CI -0.39 to -0.04] measured in 1993-95) and late life (lower Aβ42:40 [SD -0.13, 95% CI -0.23 to -0.03] and lower temporal-parietal lobe cortical thickness meta ROI [SD -0.16, 95% CI -0.28 to -0.05] measured in 2011-13). Although midlife NfL was lower in individuals with vs without midlife NAFLD, those with NAFLD exhibited a faster rate of NfL increase that accelerated over time. DISCUSSION Midlife NAFLD shows associations with AD and accumulating vascular pathology, revealing potential pathways linking liver function to dementia. Plasma biomarkers of neuropathology and neuronal injury may serve as easily measurable and dynamic indicators for monitoring the impacts of impaired liver function on brain health.
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Affiliation(s)
- Yifei Lu
- From the Departments of Epidemiology (Y.L., C.A., S.E., G.H.) and Biostatistics (T.G.), Gillings School of Global Public Health and Departments of Genetics (L.R.) and Neurology (P.P.), School of Medicine, University of North Carolina at Chapel Hill, NC; Department of Epidemiology (J.R.P., E.S.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Medicine (R.H.), Baylor College of Medicine, Houston, TX; Laboratory of Behavioral Neuroscience (K.W.), National Institute on Aging, Bethesda, MD; and Department of Epidemiology and Prevention (M.M.M.), Wake Forest University School of Medicine, Winston-Salem, NC
| | - James R Pike
- From the Departments of Epidemiology (Y.L., C.A., S.E., G.H.) and Biostatistics (T.G.), Gillings School of Global Public Health and Departments of Genetics (L.R.) and Neurology (P.P.), School of Medicine, University of North Carolina at Chapel Hill, NC; Department of Epidemiology (J.R.P., E.S.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Medicine (R.H.), Baylor College of Medicine, Houston, TX; Laboratory of Behavioral Neuroscience (K.W.), National Institute on Aging, Bethesda, MD; and Department of Epidemiology and Prevention (M.M.M.), Wake Forest University School of Medicine, Winston-Salem, NC
| | - Ron Hoogeveen
- From the Departments of Epidemiology (Y.L., C.A., S.E., G.H.) and Biostatistics (T.G.), Gillings School of Global Public Health and Departments of Genetics (L.R.) and Neurology (P.P.), School of Medicine, University of North Carolina at Chapel Hill, NC; Department of Epidemiology (J.R.P., E.S.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Medicine (R.H.), Baylor College of Medicine, Houston, TX; Laboratory of Behavioral Neuroscience (K.W.), National Institute on Aging, Bethesda, MD; and Department of Epidemiology and Prevention (M.M.M.), Wake Forest University School of Medicine, Winston-Salem, NC
| | - Keenan Walker
- From the Departments of Epidemiology (Y.L., C.A., S.E., G.H.) and Biostatistics (T.G.), Gillings School of Global Public Health and Departments of Genetics (L.R.) and Neurology (P.P.), School of Medicine, University of North Carolina at Chapel Hill, NC; Department of Epidemiology (J.R.P., E.S.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Medicine (R.H.), Baylor College of Medicine, Houston, TX; Laboratory of Behavioral Neuroscience (K.W.), National Institute on Aging, Bethesda, MD; and Department of Epidemiology and Prevention (M.M.M.), Wake Forest University School of Medicine, Winston-Salem, NC
| | - Laura Raffield
- From the Departments of Epidemiology (Y.L., C.A., S.E., G.H.) and Biostatistics (T.G.), Gillings School of Global Public Health and Departments of Genetics (L.R.) and Neurology (P.P.), School of Medicine, University of North Carolina at Chapel Hill, NC; Department of Epidemiology (J.R.P., E.S.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Medicine (R.H.), Baylor College of Medicine, Houston, TX; Laboratory of Behavioral Neuroscience (K.W.), National Institute on Aging, Bethesda, MD; and Department of Epidemiology and Prevention (M.M.M.), Wake Forest University School of Medicine, Winston-Salem, NC
| | - Elizabeth Selvin
- From the Departments of Epidemiology (Y.L., C.A., S.E., G.H.) and Biostatistics (T.G.), Gillings School of Global Public Health and Departments of Genetics (L.R.) and Neurology (P.P.), School of Medicine, University of North Carolina at Chapel Hill, NC; Department of Epidemiology (J.R.P., E.S.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Medicine (R.H.), Baylor College of Medicine, Houston, TX; Laboratory of Behavioral Neuroscience (K.W.), National Institute on Aging, Bethesda, MD; and Department of Epidemiology and Prevention (M.M.M.), Wake Forest University School of Medicine, Winston-Salem, NC
| | - Christy Avery
- From the Departments of Epidemiology (Y.L., C.A., S.E., G.H.) and Biostatistics (T.G.), Gillings School of Global Public Health and Departments of Genetics (L.R.) and Neurology (P.P.), School of Medicine, University of North Carolina at Chapel Hill, NC; Department of Epidemiology (J.R.P., E.S.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Medicine (R.H.), Baylor College of Medicine, Houston, TX; Laboratory of Behavioral Neuroscience (K.W.), National Institute on Aging, Bethesda, MD; and Department of Epidemiology and Prevention (M.M.M.), Wake Forest University School of Medicine, Winston-Salem, NC
| | - Stephanie Engel
- From the Departments of Epidemiology (Y.L., C.A., S.E., G.H.) and Biostatistics (T.G.), Gillings School of Global Public Health and Departments of Genetics (L.R.) and Neurology (P.P.), School of Medicine, University of North Carolina at Chapel Hill, NC; Department of Epidemiology (J.R.P., E.S.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Medicine (R.H.), Baylor College of Medicine, Houston, TX; Laboratory of Behavioral Neuroscience (K.W.), National Institute on Aging, Bethesda, MD; and Department of Epidemiology and Prevention (M.M.M.), Wake Forest University School of Medicine, Winston-Salem, NC
| | - Michelle M Mielke
- From the Departments of Epidemiology (Y.L., C.A., S.E., G.H.) and Biostatistics (T.G.), Gillings School of Global Public Health and Departments of Genetics (L.R.) and Neurology (P.P.), School of Medicine, University of North Carolina at Chapel Hill, NC; Department of Epidemiology (J.R.P., E.S.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Medicine (R.H.), Baylor College of Medicine, Houston, TX; Laboratory of Behavioral Neuroscience (K.W.), National Institute on Aging, Bethesda, MD; and Department of Epidemiology and Prevention (M.M.M.), Wake Forest University School of Medicine, Winston-Salem, NC
| | - Tanya Garcia
- From the Departments of Epidemiology (Y.L., C.A., S.E., G.H.) and Biostatistics (T.G.), Gillings School of Global Public Health and Departments of Genetics (L.R.) and Neurology (P.P.), School of Medicine, University of North Carolina at Chapel Hill, NC; Department of Epidemiology (J.R.P., E.S.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Medicine (R.H.), Baylor College of Medicine, Houston, TX; Laboratory of Behavioral Neuroscience (K.W.), National Institute on Aging, Bethesda, MD; and Department of Epidemiology and Prevention (M.M.M.), Wake Forest University School of Medicine, Winston-Salem, NC
| | - Gerardo Heiss
- From the Departments of Epidemiology (Y.L., C.A., S.E., G.H.) and Biostatistics (T.G.), Gillings School of Global Public Health and Departments of Genetics (L.R.) and Neurology (P.P.), School of Medicine, University of North Carolina at Chapel Hill, NC; Department of Epidemiology (J.R.P., E.S.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Medicine (R.H.), Baylor College of Medicine, Houston, TX; Laboratory of Behavioral Neuroscience (K.W.), National Institute on Aging, Bethesda, MD; and Department of Epidemiology and Prevention (M.M.M.), Wake Forest University School of Medicine, Winston-Salem, NC
| | - Priya Palta
- From the Departments of Epidemiology (Y.L., C.A., S.E., G.H.) and Biostatistics (T.G.), Gillings School of Global Public Health and Departments of Genetics (L.R.) and Neurology (P.P.), School of Medicine, University of North Carolina at Chapel Hill, NC; Department of Epidemiology (J.R.P., E.S.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Medicine (R.H.), Baylor College of Medicine, Houston, TX; Laboratory of Behavioral Neuroscience (K.W.), National Institute on Aging, Bethesda, MD; and Department of Epidemiology and Prevention (M.M.M.), Wake Forest University School of Medicine, Winston-Salem, NC
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Al Hashmi K, Giglio RV, Pantea Stoian A, Patti AM, Al Waili K, Al Rasadi K, Ciaccio M, Rizzo M. Metabolic dysfunction-associated fatty liver disease: current therapeutic strategies. Front Nutr 2024; 11:1355732. [PMID: 38567250 PMCID: PMC10985255 DOI: 10.3389/fnut.2024.1355732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 03/11/2024] [Indexed: 04/04/2024] Open
Abstract
The definition of "Metabolic Associated Fatty Liver Disease - MAFLD" has replaced the previous definition of Nonalcoholic Fatty Liver Disease (NAFLD), because cardiometabolic criteria have been added for the prevention of cardiological risk in these patients. This definition leads to an in-depth study of the bidirectional relationships between hepatic steatosis, Type 2 Diabetes Mellitus (T2DM), Cardiovascular Disease (CVD) and/or their complications. Lifestyle modification, which includes correct nutrition combined with regular physical activity, represents the therapeutic cornerstone of MAFLD. When therapy is required, there is not clear accord on how to proceed in an optimal way with nutraceutical or pharmacological therapy. Numerous studies have attempted to identify nutraceuticals with a significant benefit on metabolic alterations and which contribute to the improvement of hepatic steatosis. Several evidences are supporting the use of silymarin, berberine, curcumin, Nigella sativa, Ascophyllum nodosum, and Fucus vesiculosus, vitamin E, coenzyme Q10 and Omega-3. However, more evidence regarding the long-term efficacy and safety of these compounds are required. There is numerous evidence that highlights the use of therapies such as incretins or the use of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors or other similar therapies which, by assisting existing therapies for pathologies such as diabetes, hypertension, insulin resistance, have given a breakthrough in prevention and the reduction of cardiometabolic risk. This review gave an overview of the current therapeutic strategies that are expected to aid in the treatment and prevention of MAFLD.
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Affiliation(s)
- Khamis Al Hashmi
- Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Rosaria Vincenza Giglio
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
- Department of Laboratory Medicine, University Hospital, Palermo, Italy
| | - Anca Pantea Stoian
- Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Angelo Maria Patti
- Internal Medicine Unit, “Vittorio Emanuele II” Hospital, Castelvetrano, Italy
| | - Khalid Al Waili
- Department of Biochemistry, Sultan Qaboos University Hospital, Muscat, Oman
| | - Khalid Al Rasadi
- Department of Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
- Medical Research Center, Sultan Qaboos University, Muscat, Oman
| | - Marcello Ciaccio
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
- Department of Laboratory Medicine, University Hospital, Palermo, Italy
| | - Manfredi Rizzo
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
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Xu T, Wang L, Chang N, Li S, Jiao B, Zhang S, Wang X. CT-Diagnosed Non-Alcoholic Fatty Liver Disease as a Risk Predictor of Symptomatic Carotid Plaque and Cerebrovascular Symptoms. Angiology 2024:33197241227501. [PMID: 38232089 DOI: 10.1177/00033197241227501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2024]
Abstract
We aimed to test whether computed tomography (CT)-diagnosed Non-Alcoholic Fatty Liver Disease (NAFLD) is a risk factor for cerebrovascular symptoms in patients with suspected atherosclerotic disease. A total of 550 patients (mean age 65.2 ± 8.8 years, 370 males) with carotid plaques who underwent carotid computed tomographic angiography (CTA) and unenhanced abdominal CT were retrospectively analyzed. NAFLD was diagnosed by abdominal CT. Carotid CTA assessed the presence of carotid artery stenosis or plaque. The relationship between NAFLD and cerebrovascular symptoms was analyzed using generalized estimating equations and receiver operating characteristic (ROC) analysis. The prevalence of NAFLD was significantly higher in symptomatic patients (76.5 vs 9.8%; P < .001). After adjusting for several confounding factors (e.g., hypertension and hyperlipidemia), univariate and multivariate logic regression analysis revealed that NAFLD was still strongly associated with cerebrovascular symptoms (odds ratio, 22.81; 95% CI 13.03-39.93; P < .001). ROC analysis showed that the area under the curve for discriminating symptomatic and asymptomatic plaques using NAFLD measurements was 0.833, with a sensitivity of 76.5% and a specificity of 90.2%. NAFLD is strongly associated with an increased risk of cerebrovascular symptoms. It may be an important predictor of symptomatic carotid plaque and cerebrovascular symptoms.
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Affiliation(s)
- Tianqi Xu
- Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong University, Jinan, China
| | - Li Wang
- Physical Examination Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Na Chang
- Jinan Vocational College of Nursing, Jinan, China
| | - Sha Li
- Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong University, Jinan, China
| | - Bingxuan Jiao
- Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong University, Jinan, China
| | - Shuai Zhang
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong University, Jinan, China
| | - Ximing Wang
- Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong University, Jinan, China
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Jin D, Jin S, Zhou T, Cui Z, Guo B, Li G, Zhang C. Regional variation in NAFLD prevalence and risk factors among people living with HIV in Europe: a meta-analysis. Front Public Health 2024; 11:1295165. [PMID: 38259755 PMCID: PMC10802187 DOI: 10.3389/fpubh.2023.1295165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 12/08/2023] [Indexed: 01/24/2024] Open
Abstract
Background and Aim Europe faces an elevated risk of nonalcoholic fatty liver disease (NAFLD) among people living with HIV (PLWH), contributing to the region's highest global burden of NAFLD. However, the prevalence of NAFLD across various European countries and regions remains unclear. This study aims to investigate the prevalence and risk factors associated with NAFLD among PLWH across European countries. Methods A systematic search was conducted across four databases: PubMed, Embase, Web of Science, and Cochrane Library. Data on the prevalence of NAFLD, nonalcoholic steatohepatitis (NASH), and fibrosis, as well as the associated risk factors, were collected among PLWH in Europe. Results Thirty-six studies from 13 European nations were included. The prevalence of NAFLD, NASH, and fibrosis were 42% (95%CI 37-48), 35% (95%CI 21-50) and 13% (95%CI 10-15), respectively. Male gender, BMI, waist circumference, Diabetes, hypertension, metabolic syndrome, dyslipidemia, triglycerides, HDL, LDL, ALT, AST, and years on antiretroviral therapy (ART) were found to be risk factors for NAFLD. High BMI and triglycerides were associated with NASH. Patients with high BMI and triglycerides are at increased risk of significant liver fibrosis. Conclusion The high prevalence of NAFLD, NASH, and fibrosis among PLWH in Europe highlights the need for early screening, intervention, and increased research focus on adolescents living with HIV. Furthermore, the significant variations observed between countries and regions underscore the influence of related risk factors.
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Affiliation(s)
- Dachuan Jin
- Clinical Laboratory, Sixth People’s Hospital of Zhengzhou, Zhengzhou, China
| | - Shunqin Jin
- Department of Radiology, Hebei Medical University, Shijiazhuang, China
| | - Tao Zhou
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
| | - Zhongfeng Cui
- Clinical Laboratory, Sixth People’s Hospital of Zhengzhou, Zhengzhou, China
| | - Baoqiang Guo
- Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, United Kingdom
| | - Guangming Li
- Department of Liver Disease, Sixth People’s Hospital of Zhengzhou, Zhengzhou, China
| | - Chunming Zhang
- Department of General Surgery, Sixth People’s Hospital of Zhengzhou, Zhengzhou, China
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9
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Nazeer B, Khawar MB, Khalid MU, Hamid SE, Rafiq M, Abbasi MH, Sheikh N, Ali A, Fatima H, Ahmad S. Emerging role of lipophagy in liver disorders. Mol Cell Biochem 2024; 479:1-11. [PMID: 36943663 DOI: 10.1007/s11010-023-04707-1] [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: 02/13/2022] [Accepted: 03/10/2023] [Indexed: 03/23/2023]
Abstract
Lipophagy is a selective degradation of lipids by a lysosomal-mediated pathway, and dysregulation of lipophagy is linked with the pathological hallmark of many liver diseases. Downregulation of lipophagy in liver cells results in abnormal accumulation of LDs (Lipid droplets) in hepatocytes which is a characteristic feature of several liver pathologies such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Contrarily, upregulation of lipophagy in activated hepatic stellate cells (HSCs) is associated with hepatic fibrosis and cirrhosis. Lipid metabolism reprogramming in violent cancer cells contributes to the progression of liver cancer. In this review, we have summarized the recent studies focusing on various components of the lipophagic machinery that can be modulated for their potential role as therapeutic agents against a wide range of liver diseases.
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Affiliation(s)
- Bismillah Nazeer
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Muhammad Babar Khawar
- Applied Molecular Biology and Biomedicine Lab, Department of Zoology, University of Narowal, Narowal, Pakistan.
| | - Muhammad Usman Khalid
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Syeda Eisha Hamid
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Mussarat Rafiq
- Cell and Molecular Biology Lab, Institute of Zoology, University of the Punjab, Lahore, Pakistan
| | | | - Nadeem Sheikh
- Cell and Molecular Biology Lab, Institute of Zoology, University of the Punjab, Lahore, Pakistan.
| | - Ahmad Ali
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Hooriya Fatima
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Sadia Ahmad
- Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
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Hwang G, Seo H, Park JC. Copine7 deficiency leads to hepatic fat accumulation via mitochondrial dysfunction. Heliyon 2023; 9:e21676. [PMID: 37954344 PMCID: PMC10637907 DOI: 10.1016/j.heliyon.2023.e21676] [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: 08/14/2023] [Revised: 10/25/2023] [Accepted: 10/25/2023] [Indexed: 11/14/2023] Open
Abstract
Objective Mitochondrial dysfunction affects hepatic lipid homeostasis and promotes ROS generation. Copine7 (CPNE7) belongs to the ubiquitous copine family of calcium-dependent phospholipid binding proteins. CPNE7 has a high calcium ion binding affinity and the capacity to scavenge reactive oxygen species (ROS). A recent study reported that abnormalities in fatty acid and lipid metabolism were linked to the gene variant of CPNE7. Therefore, the purpose of this study is to examine the role of Cpne7 in hepatic lipid metabolism based on mitochondrial function. Methods Lipid metabolism, mitochondrial function, and ROS production were investigated in high-fat diet (HFD)-fed Cpne7-/- mice and H2O2-damaged HepG2 hepatocytes following CPNE7 silencing or overexpression. Results Cpne7 deficiency promoted severe hepatic steatosis in the HFD-induced NAFLD model. More importantly, mitochondrial dysfunction was observed along with an imbalance of mitochondrial dynamics in the livers of HFD-fed Cpne7-/-mice, resulting in high ROS levels. Similarly, CPNE7-silenced HepG2 hepatocytes showed high ROS levels, mitochondrial dysfunction, and increased lipid contents. On the contrary, CPNE7-overexpressed HepG2 cells showed low ROS levels, enhanced mitochondrial function and decreased lipid contents under H2O2-induced oxidative stress. Conclusions In the liver, Cpne7 deficiency causes excessive ROS formation and mitochondrial dysfunction, which aggravates lipid metabolism abnormalities. These findings provide evidence that Cpne7 deficiency contributes to the pathogenesis of NAFLD, suggesting Cpne7 as a novel therapeutic target for NAFLD.
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Affiliation(s)
- Geumbit Hwang
- Laboratory for the Study of Regenerative Dental Medicine, Department of Oral Histology-Developmental Biology & Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
- Regenerative Dental Medicine R & D Center, HysensBio, Co., Ltd., 10 Dwitgol-ro, Gwacheon-si, Gyeonggi-do, Republic of Korea
| | - Hyejin Seo
- Laboratory for the Study of Regenerative Dental Medicine, Department of Oral Histology-Developmental Biology & Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Joo-Cheol Park
- Laboratory for the Study of Regenerative Dental Medicine, Department of Oral Histology-Developmental Biology & Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
- Regenerative Dental Medicine R & D Center, HysensBio, Co., Ltd., 10 Dwitgol-ro, Gwacheon-si, Gyeonggi-do, Republic of Korea
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11
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Li F, Zhang Z, Bai Y, Che Q, Cao H, Guo J, Su Z. Glucosamine Improves Non-Alcoholic Fatty Liver Disease Induced by High-Fat and High-Sugar Diet through Regulating Intestinal Barrier Function, Liver Inflammation, and Lipid Metabolism. Molecules 2023; 28:6918. [PMID: 37836761 PMCID: PMC10574579 DOI: 10.3390/molecules28196918] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/28/2023] [Accepted: 10/01/2023] [Indexed: 10/15/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a liver disease syndrome. The prevalence of NAFLD has continued to increase globally, and NAFLD has become a worldwide public health problem. Glucosamine (GLC) is an amino monosaccharide derivative of glucose. GLC has been proven to not only be effective in anti-inflammation applications, but also to modulate the gut microbiota effectively. Therefore, in this study, the therapeutic effect of GLC in the NAFLD context and the mechanisms underlying these effects were explored. Specifically, an NAFLD model was established by feeding mice a high-fat and high-sugar diet (HFHSD), and the HFHSD-fed NAFLD mice were treated with GLC. First, we investigated the effect of treating NAFLD mice with GLC by analyzing serum- and liver-related indicator levels. We found that GLC attenuated insulin resistance and inflammation, increased antioxidant function, and attenuated serum and liver lipid metabolism in the mice. Then, we investigated the mechanism underlying liver lipid metabolism, inflammation, and intestinal barrier function in these mice. We found that GLC can improve liver lipid metabolism and relieve insulin resistance and oxidative stress levels. In addition, GLC treatment increased intestinal barrier function, reduced LPS translocation, and reduced liver inflammation by inhibiting the activation of the LPS/TLR4/NF-κB pathway, thereby effectively ameliorating liver lesions in NAFLD mice.
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Affiliation(s)
- Feng Li
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Zhengyan Zhang
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Qishi Che
- Guangzhou Rainhome Pharm & Tech Co., Ltd., Science City, Guangzhou 510663, China
| | - Hua Cao
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China;
| | - Jiao Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
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Mujlli G, Mahzari M, Alslamah I, Syed J, Omair A, Abulmeaty M, Aldisi D. Non-alcoholic Fatty Liver in Children and Adolescents in Saudi Arabia. Cureus 2023; 15:e46380. [PMID: 37927726 PMCID: PMC10620069 DOI: 10.7759/cureus.46380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/02/2023] [Indexed: 11/07/2023] Open
Abstract
Objectives This study aims to describe the disease parameters of children and adolescents diagnosed with non-alcoholic fatty liver disease (NAFLD) in Saudi Arabia. It also investigates the disease's progression and compares clinical, biochemical, and radiological parameters at baseline and follow-up of patients with NAFLD. This study was done between two groups of patients: obese and those of average body weight. Methods A retrospective cohort study was conducted between 2014 and 2018 through retrieved data from medical records. It included all children aged between six to 18 years diagnosed with NAFLD. Medical history was taken from each medical record, liver function test results, cholesterol, blood pressure readings, and body weight. Data have been restored from King Abdullah Specialist Children's Hospital (KASCH), Security Forces Hospital (SFH), and King Khalid University Hospital (KKUH). Results A total of 116 subjects met the inclusion criteria; 65 (56%) were male, and 81 (70%) were obese. The majority of subjects (n=112) had mild NAFLD, with (71%) obese and (29%) non-obese, followed by moderate NAFLD with 50% among obese and non-obese (N=2), and non-alcoholic steatohepatitis (NASH) with 100% non-obese (N=2). Data showed that patients' proportion of obese to non-obese is 70% (N=81) to 30% (N=35), respectively. Conclusion NAFLD was found to affect obese children and adolescents more than non-obese, and male patients had a higher proportion of NAFLD than females. Also, obese patients had more advanced stages of NAFLD than non-obese patients. Finally, most subjects had been diagnosed with mild stage while a few had developed NASH.
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Affiliation(s)
- Gadah Mujlli
- Simulation and Skills Development Center, Princess Nourah Bint Abdulrahman University, Riyadh, SAU
- Department of Community Health, King Saud University, Riyadh, SAU
| | - Moeber Mahzari
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, SAU
- Department Endocrinology, Ministry of National Guard Health Affairs, Riyadh, SAU
- King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, SAU
| | - Ibrahim Alslamah
- Simulation and Skills Development Center, Princess Nourah Bint Abdulrahman University, Riyadh, SAU
| | - Jamil Syed
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, SAU
- Department of Pediatrics, King Abdullah Specialized Children Hospital, Riyadh, SAU
| | - Aamir Omair
- Department of Medical Education, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, SAU
| | - Mahumoud Abulmeaty
- Department of Community Health, King Saud University, Riyadh, SAU
- Department of Medical Physiology, Zagazig University, Zagazig, EGY
| | - Dara Aldisi
- Department of Community Health, King Saud University, Riyadh, SAU
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Mohseni-Moghaddam P, Khanmohammadi M, Roghani M. Literature review on hepatoprotective effects of diosgenin: possible mechanisms of action. Front Pharmacol 2023; 14:1226548. [PMID: 37767400 PMCID: PMC10520708 DOI: 10.3389/fphar.2023.1226548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 08/31/2023] [Indexed: 09/29/2023] Open
Abstract
Liver diseases are among the major causes of death worldwide. Alcohol consumption, obesity, diabetes mellitus, viral infection, and drug-induced liver injury are common risk factors for the development of liver diseases. Diosgenin is a herbal steroidal sapogenin with hepatoprotective properties. This phytosteroid modulates lipid profile and prevents liver injury and fibrosis, metabolic associated fatty liver disease (MAFLD), steatohepatitis, and diabetes mellitus. Different mechanisms have been presented underlying the therapeutic properties of diosgenin. Diosgenin with antioxidant activity and ability to inhibit pro-inflammatory and apoptotic mediators as well as modulating gut microbiota is able to protect the liver. This literature overview summarizes the previously published studies regarding the hepatoprotective function of diosgenin against liver injury in different conditions with an emphasis on possible underlying mechanisms.
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Affiliation(s)
- Parvaneh Mohseni-Moghaddam
- Department of Physiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Manijeh Khanmohammadi
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Mehrdad Roghani
- Neurophysiology Research Center, Shahed University, Tehran, Iran
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McDonough DJ, Mathew M, Pope ZC, Schreiner PJ, Jacobs DR, VanWagner LB, Carr JJ, Terry JG, Gabriel KP, Reis JP, Pereira MA. Aerobic and Muscle-Strengthening Physical Activity, Television Viewing, and Nonalcoholic Fatty Liver Disease: The CARDIA Study. J Clin Med 2023; 12:5603. [PMID: 37685671 PMCID: PMC10488389 DOI: 10.3390/jcm12175603] [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: 07/17/2023] [Revised: 08/22/2023] [Accepted: 08/24/2023] [Indexed: 09/10/2023] Open
Abstract
BACKGROUND The prevalence of non-alcoholic fatty liver disease (NAFLD) in U.S. adults is over 30%, yet the role of lifestyle factors in the etiology of NAFLD remains understudied. We examined the associations of physical activity, by intensity and type, and television viewing with prevalent NAFLD. METHODS Cross-sectional analysis of a population-based sample of 2726 Black (49%) and White (51%) adults (Mean (SD) age, 50 (3.6) years; 57.3% female) from the CARDIA study. Exposures were aerobic activity by intensity (moderate, vigorous; hours/week); activity type (aerobic, muscle-strengthening; hours/week); and television viewing (hours/week), examined concurrently in all models and assessed by validated questionnaires. Our outcome was NAFLD (liver attenuation < 51 Hounsfield Units), measured by non-contrast computed tomography, after exclusions for other causes of liver fat. Covariates were sex, age, race, study center, education, diet quality, smoking status, alcohol consumption, and body mass index or waist circumference. RESULTS 648 participants had NAFLD. In the fully adjusted modified Poisson regression model, the risk ratios per interquartile range of each exposure were moderate-intensity aerobic activity, 1.10 (95% CI, 0.97-1.26); vigorous-intensity aerobic activity, 0.72 (0.63-0.82); muscle-strengthening activity, 0.89 (0.80-1.01); and television viewing, 1.20 (1.10-1.32). Relative to less active participants with higher levels of television viewing, those who participated in ≥2 h/week of both vigorous-intensity aerobic and muscle-strengthening activity and <7 h/week of television viewing had 65% lower risk of NAFLD (risk ratio = 0.35, 95% CI = 0.23-0.51). CONCLUSION Adults who follow public health recommendations for vigorous-aerobic and muscle-strengthening activity, as well as minimize television viewing, are considerably less likely to have NAFLD than those who do not follow the recommendations and who have relatively high levels of television viewing.
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Affiliation(s)
- Daniel J. McDonough
- Division of Epidemiology & Community Health, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA; (M.M.); (P.J.S.); (D.R.J.J.); (M.A.P.)
| | - Mahesh Mathew
- Division of Epidemiology & Community Health, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA; (M.M.); (P.J.S.); (D.R.J.J.); (M.A.P.)
| | - Zachary C. Pope
- Well Living Lab, Rochester, NY 55902, USA;
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, NY 14625, USA
| | - Pamela J. Schreiner
- Division of Epidemiology & Community Health, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA; (M.M.); (P.J.S.); (D.R.J.J.); (M.A.P.)
| | - David R. Jacobs
- Division of Epidemiology & Community Health, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA; (M.M.); (P.J.S.); (D.R.J.J.); (M.A.P.)
| | - Lisa B. VanWagner
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
| | - John Jeffrey Carr
- Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA; (J.J.C.); (J.G.T.)
| | - James G. Terry
- Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA; (J.J.C.); (J.G.T.)
| | - Kelley Pettee Gabriel
- Department of Epidemiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Jared P. Reis
- National Heart Lung and Blood Institute, Bethesda, MD 20892, USA;
| | - Mark A. Pereira
- Division of Epidemiology & Community Health, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA; (M.M.); (P.J.S.); (D.R.J.J.); (M.A.P.)
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Fotschki B, Sójka M, Kosmala M, Juśkiewicz J. Prebiotics Together with Raspberry Polyphenolic Extract Mitigate the Development of Nonalcoholic Fatty Liver Diseases in Zucker Rats. Nutrients 2023; 15:3115. [PMID: 37513533 PMCID: PMC10385479 DOI: 10.3390/nu15143115] [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: 06/23/2023] [Revised: 07/09/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Previous studies suggested that dietary supplementation with prebiotic fructooligosaccharides (FOSs) and polyphenols could mitigate disorders related to the first stage of nonalcoholic fatty liver disease (NAFLD) induced by an obesogenic diet. Therefore, this experiment aimed to address whether the health-promoting potential of raspberry polyphenols together with FOSs can regulate advanced-stage NAFLD in Zucker rats genetically predisposed to develop obesity. The addition of FOSs and raspberry polyphenolic extract to the diet reduced liver fat accumulation and triglyceride, free fatty acid, and total cholesterol levels in the liver. The elevated GSH/GSSG ratio and reduced malondialdehyde content indicated that the liver antioxidant potential was considerably increased. The treatment also lowered the plasma aminotransferase and alkaline phosphatase activities and collagen type IV levels. Insulin levels were decreased, but glucose levels remained constant, indicating greater insulin sensitivity. These changes may result from the upregulation of FXR and AHR receptors in the liver, which are responsible for regulating lipid metabolism and glucose and bile acid synthesis. The reduced bile acid levels in the cecal contents confirmed the activation of liver mechanisms. In conclusion, dietary enrichment with FOSs and raspberry polyphenolic extract has sufficient health-promoting potential to regulate liver metabolism, oxidative stress, and inflammation related to NAFLD development in obese Zucker rats.
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Affiliation(s)
- Bartosz Fotschki
- Division of Food Science, Institute of Animal Reproduction and Food Research, Tuwima 10, 10-748 Olsztyn, Poland
| | - Michał Sójka
- Institute of Food Technology and Analysis, Łódź University of Technology, Stefanowskiego 4/10, 90-924 Łódź, Poland
| | - Monika Kosmala
- Institute of Food Technology and Analysis, Łódź University of Technology, Stefanowskiego 4/10, 90-924 Łódź, Poland
| | - Jerzy Juśkiewicz
- Division of Food Science, Institute of Animal Reproduction and Food Research, Tuwima 10, 10-748 Olsztyn, Poland
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Teng S, Zheng N, Al-Huqail AA, Lu Y, Ali E, Ali HE, Zhao H. Effect of nanoparticle macroalgae in the treatment of fatty liver disease using logistic regression, and support vector machine. ENVIRONMENTAL RESEARCH 2023; 224:115426. [PMID: 36781010 DOI: 10.1016/j.envres.2023.115426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/26/2023] [Accepted: 02/03/2023] [Indexed: 06/18/2023]
Abstract
One of the major health issues facing people worldwide is liver fibrosis. Liver fibrosis may be brought on by long-term exposure to harmful substances, medicines, and microorganisms. The development of liver fibrosis in children was particularly worrying due to their longer life-span, which was possibly related to a great risk of developing long-term complications. Marine algae species have provided a biological variety in the research phase of novel approaches to the treatment of numerous ailments. Marine macroalgae have recently been the subject of research due to their rich bioactive chemical composition and potential for the production of various nutraceuticals. Macroalgae are potentially excellent sources of bioactive substances with particular and distinct biological activity when compared to their terrestrial equivalents. Macroalgae in diverse marine cases offer a few biologically active metabolites, comprising sterols, polyunsaturated fatty acids, carotenoids, oligosaccharides, polysaccharides, proteins, polyphenols, vitamins, and minerals. Accordingly, there is great interest in their high potential for supporting immunomodulatory, antimicrobial, antidiabetic, antitumoral, anti-inflammatory, antiangiogenic, and neuroprotective properties. Using an experimental model, the current research intends to collect data on the therapeutic value of macroalgae nanoparticles for fatty liver disease. The researchers' goal of predicting illnesses from the extensive medical datasets is quite difficult. The purpose of this research is to assess the protective effects of a seaweed, Padina pavonia (PP), on liver fibrosis caused by carbon tetrachloride (CCl4). This research presents two models of logistic regression (LR) and support vector machines (SVM) for predicting the likelihood of liver disease incidence. The performance of the model was evaluated using a dataset. PP macro-algae considerably reduce the high blood concentrations of aminotransferases, alkaline phosphatases, and lactate dehydrogenases, as well as causing a considerable (p < 0.05) decrease in serum bilirubin levels. In addition to improving kidney function (urea and creatinine), algal extracts enhance fat metabolism (triglycerides and cholesterol). With an accuracy rate of 70.2%, a sensitivity of 92.3%, a specificity of 74.7%, a type I error of 9.1%, and a type II error of 21.0%, the predictive model has demonstrated excellent performance. The model validated laboratory tests' ability to predict illness (age; direct bilirubin (DB), total proteins (TP), and albumin (ALB). These classifier methods are compared on the basis of their execution time and classification accuracy.
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Affiliation(s)
- Shu Teng
- Department of Pediatric Infection, Hangzhou Children's Hospital, Hangzhou, 310014, China
| | - Nan Zheng
- Zhejiang University of Traditional Chinese Medicine, Hangzhou, 310000, China
| | - Arwa A Al-Huqail
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O.Box 84428, Riyadh, 11671, Saudi Arabia.
| | - Yanjie Lu
- Hangzhou Dianzi University, Hangzhou, 310018, China
| | - Elimam Ali
- Department of Civil Engineering, College of Engineering in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | - H Elhosiny Ali
- Department of Physics, Faculty of Science, King Khalid University, P.O. Box 9004, Abha, Saudi Arabia; Physics Department, Faculty of Science, Zagazig University, 44519, Zagazig, Egypt; Research Center for Advanced Materials Science (RCAMS), King Khalid University, Abha, 61413, P.O. Box 9004, Saudi Arabia
| | - Huajun Zhao
- University of Traditional Chinese Medicine, Hangzhou, 310000, China.
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Lei F, Wang XM, Wang C, Huang X, Liu YM, Qin JJ, Zhang P, Ji YX, She ZG, Cai J, Li HP, Zhang XJ, Li H. Metabolic dysfunction-associated fatty liver disease increased the risk of subclinical carotid atherosclerosis in China. Front Endocrinol (Lausanne) 2023; 14:1109673. [PMID: 37082131 PMCID: PMC10110917 DOI: 10.3389/fendo.2023.1109673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 03/21/2023] [Indexed: 04/07/2023] Open
Abstract
Background and aimsMetabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to substitute NAFLD in 2020. This new term highlights the systematic metabolic disturbances that accompany fatty liver. We evaluated the correlations between MAFLD and subclinical carotid atherosclerosis (SCA) based on a nationwide health examination population in China.MethodsWe performed a nationwide cross-sectional population and a Beijing retrospective cohort from 2009 to 2017. SCA was defined as elevated carotid intima-media thickness. The multivariable logistic and Cox models were used to analyze the association between MAFLD and SCA.Results153,482 participants were included in the cross-sectional study. MAFLD was significantly associated with SCA in fully adjusted models, with an odds ratio of 1.66; 95% confidence interval (CI): 1.62-1.70. This association was consistent in the cohort, with a hazard ratio (HR) of 1.31. The association between baseline MAFLD and incident SCA increased with hepatic steatosis severity. Subgroup analysis showed an interaction between age and MAFLD, with a higher risk in younger groups (HR:1.67, 95% CI: 1.17-2.40).ConclusionIn this large cross-section and cohort study, MAFLD was significantly associated with the presence and development of SCA. Further, the risk was higher among MAFLD individuals with high hepatic steatosis index and young adults.
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Affiliation(s)
- Fang Lei
- Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
| | - Xiao-Ming Wang
- Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
| | - Changquan Wang
- Department of Neurology, Huanggang Central Hospital of Yangtze University, Huanggang, China
- Huanggang Institute of Translational Medicine, Huanggang Central Hospital of Yangtze University, Huanggang, China
| | - Xuewei Huang
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Ye-Mao Liu
- Institute of Model Animal, Wuhan University, Wuhan, China
- Huanggang Institute of Translational Medicine, Huanggang Central Hospital of Yangtze University, Huanggang, China
- Department of Cardiology, Huanggang Central Hospital of Yangtze University, Huanggang, China
| | - Juan-Juan Qin
- Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
| | - Peng Zhang
- Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
| | - Yan-Xiao Ji
- Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
| | - Zhi-Gang She
- Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
| | - Jingjing Cai
- Institute of Model Animal, Wuhan University, Wuhan, China
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Huo-ping Li
- Huanggang Institute of Translational Medicine, Huanggang Central Hospital of Yangtze University, Huanggang, China
- Department of Cardiology, Huanggang Central Hospital of Yangtze University, Huanggang, China
- *Correspondence: Hongliang Li, ; Xiao-Jing Zhang, ; Huo-ping Li,
| | - Xiao-Jing Zhang
- Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
- *Correspondence: Hongliang Li, ; Xiao-Jing Zhang, ; Huo-ping Li,
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
- Huanggang Institute of Translational Medicine, Huanggang Central Hospital of Yangtze University, Huanggang, China
- Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China
- *Correspondence: Hongliang Li, ; Xiao-Jing Zhang, ; Huo-ping Li,
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Marschner RA, Roginski AC, Ribeiro RT, Longo L, Álvares-da-Silva MR, Wajner SM. Uncovering Actions of Type 3 Deiodinase in the Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD). Cells 2023; 12:cells12071022. [PMID: 37048095 PMCID: PMC10093729 DOI: 10.3390/cells12071022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/16/2023] [Accepted: 03/23/2023] [Indexed: 03/29/2023] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) has gained worldwide attention as a public health problem. Nonetheless, lack of enough mechanistic knowledge restrains effective treatments. It is known that thyroid hormone triiodothyronine (T3) regulates hepatic lipid metabolism, and mitochondrial function. Liver dysfunction of type 3 deiodinase (D3) contributes to MAFLD, but its role is not fully understood. Objective: To evaluate the role of D3 in the progression of MAFLD in an animal model. Methodology: Male/adult Sprague Dawley rats (n = 20) were allocated to a control group (2.93 kcal/g) and high-fat diet group (4.3 kcal/g). Euthanasia took place on the 28th week. D3 activity and expression, Uncoupling Protein 2 (UCP2) and type 1 deiodinase (D1) expression, oxidative stress status, mitochondrial, Krebs cycle and endoplasmic reticulum homeostasis in liver tissue were measured. Results: We observed an increase in D3 activity/expression (p < 0.001) related to increased thiobarbituric acid reactive substances (TBARS) and carbonyls and diminished reduced glutathione (GSH) in the MAFLD group (p < 0.05). There was a D3-dependent decrease in UCP2 expression (p = 0.01), mitochondrial capacity, respiratory activity with increased endoplasmic reticulum stress in the MAFLD group (p < 0.001). Surprisingly, in an environment with lower T3 levels due to high D3 activity, we observed an augmented alpha-ketoglutarate dehydrogenase (KGDH) and glutamate dehydrogenase (GDH) enzymes activity (p < 0.05). Conclusion: Induced D3, triggered by changes in the REDOX state, decreases T3 availability and hepatic mitochondrial capacity. The Krebs cycle enzymes were altered as well as endoplasmic reticulum stress. Taken together, these results shed new light on the role of D3 metabolism in MAFLD.
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Affiliation(s)
- Rafael Aguiar Marschner
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil
| | - Ana Cristina Roginski
- Post-Graduate Program in Biochemestry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, RS, Brazil
| | - Rafael Teixeira Ribeiro
- Post-Graduate Program in Biochemestry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, RS, Brazil
| | - Larisse Longo
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil
| | - Mário Reis Álvares-da-Silva
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil
- Department of Internal Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, RS, Brazil
| | - Simone Magagnin Wajner
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil
- Department of Internal Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, RS, Brazil
- Correspondence:
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Calluna vulgaris Crude Extract Reverses Liver Steatosis and Insulin Resistance-Associated-Brain Lesion Induced by CCl4 Administration. SEPARATIONS 2023. [DOI: 10.3390/separations10020094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Fatty liver (FL) is one of the most prevalent diseases in the world, characterized by insulin resistance and hyperlipidemia, which consequently lead to neurodegenerative disorders through the induction of oxidative stress-inflammatory axis, which alters the neurotransmitters’ levels. Calluna vulgaris (CV), also known as heather, has anti-inflammatory and antidepressant properties, making it a promising candidate for treating steatosis and brain lesions. This study aimed to assess the prophylactic and therapeutic effect of CV extract on brain dysfunction associated with steatosis. FL was induced in rats by CCl4 oral administration (50 µL/Kg in olive oil three times/week) for six weeks. The protection group received 200 mg/kg CV extract orally for two weeks before and two weeks during FL induction, while the treatment group was orally administered CV extract after FL induction for one month. The biochemical parameters revealed that CCl4 administration induced hepatotoxicity as blood-liver function parameters (AST, ALT, ALP, protein, and LDH) were increased by 1.8, 1.4, 2, 2.4, and 1.2-fold, respectively. Moreover, insulin resistance was characterized by a two-fold increase in the glucose, insulin, and lipid profile when compared to control one, at p < 0.05. Steatosis liver demonstrated a two-fold increase in all following parameters— acetaldehyde (AC), prooxidant (TBARS), acetylcholine esterase (AChE), monoamine oxidase (MAO), hyaluronidase, and ATPase—when compared to control one, at p < 0.05. CCl4 administration led to brain lesions where the brain level of TBARS, insulin, cholesterol, AChE, and MAO was progressively increased by 2, 1.6, 2.2, 4, and 1.6-fold, respectively, that was associated with reduced glucose (8-fold) and GSH (2-fold) than that of control level, at p < 0.05. CV extract as a prophylactic and therapeutic agent increased GSH and decreased TBARS of both the liver and brain than that of induced group, at p < 0.05, normalized the activities of AChE and MAO, and increased insulin sensitivity where they successfully decreased the HOMA-IR, glucose, TG, and cholesterol compared to than that of induced group, at p < 0.05. This positive effect of CV extract contributed to the presence of polyphenolic compounds such as catechins (5.501 ± 0.056 µg/g extract), gallic (3.525 ± 0.143 µg/g) extract, and protocatechuic acid (2.719 ± 0.132 µg/g extract). Therefore, we concluded that FL induced brain dysfunction through the formation of ROS and elevation of insulin and lipid inside the brain tissue, which alter the amount of neurotransmitter and cellular energy production. Rich in polyphenolic compounds, CV extract functions as an antioxidant, antidiabetic, hepatoprotective, inhibitor of neurotransmitter catabolizing enzymes, and a regulator for energy production. Therefore, it can be used as a preventative or treatment for NAFLD and brain damage.
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20
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Micomyiza C, Zou B, Li Y. An effective automatic segmentation of abdominal adipose tissue using a convolution neural network. Diabetes Metab Syndr 2022; 16:102589. [PMID: 35995029 DOI: 10.1016/j.dsx.2022.102589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 07/29/2022] [Accepted: 07/31/2022] [Indexed: 10/15/2022]
Abstract
BACKGROUND AND AIMS Computer-aided diagnosis and prognosis rely heavily on fully automatic segmentation of abdominal fat tissue using Emission Tomography images. The identification of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in abdomen fat faces two main challenges: (1) the great difficulties in comparison to multi-stage semantic segmentation (VAT and SAT), and (2) the subtle differences due to the high similarity of the two classes in abdomen fat and complicated VAT distribution. METHODS In this research, we built an automated convolutional neural network (A-CNN) for segmenting Abdominal adipose tissue (AAT) from radiology images. RESULTS We developed a point-to-point design for the A-CNN learning process, wherein the representing features might be learned together with a hybrid feature extraction technique. We tested the proposed model on a CT dataset and evaluated it to existing CNN models. Furthermore, our suggested approach, A-CNN, outperformed existing deep learning methods regarding segmentation outcomes, notably in the AAT segment. CONCLUSIONS Proposed method is extremely fast with remarkable performance on limited-scale low dose CT-scanning and demonstrates the strength in providing an efficient computer-aimed tool for segmentation of AAT in the clinic.
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Affiliation(s)
- Carine Micomyiza
- School of Computer Science and Engineering, Central South University, Changsha, 410083, China
| | - Beiji Zou
- School of Computer Science and Engineering, Central South University, Changsha, 410083, China
| | - Yang Li
- School of Computer Science and Engineering, Central South University, Changsha, 410083, China.
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21
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Proteomic analysis of the effect of high-fat-diet and voluntary physical activity on mouse liver. PLoS One 2022; 17:e0273049. [PMID: 35981048 PMCID: PMC9387828 DOI: 10.1371/journal.pone.0273049] [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: 01/29/2022] [Accepted: 08/01/2022] [Indexed: 11/20/2022] Open
Abstract
Nonalcoholic fatty liver disease (NALFD), characterized by an abnormal accumulation of triglycerides in hepatocytes, is closely linked to insulin resistance, metabolic syndrome, and changes in lipogenesis in the liver. The accumulation of hepatic lipids can lead to a range of pathologies from mild steatosis to severe cirrhosis. Endurance exercise is known to ameliorate the adverse health effects of NAFLD. Therefore, we aimed to investigate the effect of voluntary wheel running (VWR) on the metabolic changes in the livers of high-fat diet (HFD)-induced NAFLD mice and used LC-MS/MS (Liquid chromatography–mass spectrometry) to determine whether the tested intervention affected the protein expression profiles of the mouse livers. Male C57BL/6 mice were randomly divided into three groups: control (CON), high-fat diet sedentary group (HFD), high-fat diet VWR group (HFX). HFX group performed voluntary wheel running into individually cages, given a high-fat diet for 12 weeks. Food consumption, body weight, and running distance were measured every week. Using 2D (2-dimensional)-gel electrophoresis, we detected and quantitatively analyzed the protein expression with >2.0-fold change in the livers of HFD-fed mice, HFD-fed exercise (HFX) mice, and chow-fed mice. Body weight was significantly increased in HFD compared to CON (P < 0.05). The 2D-gel electrophoresis analysis indicated that there was a difference between CON and HFD groups, showing 31 increased and 27 decreased spots in the total 302 paired spots in the HFD group compared to CON. The analysis showed 43 increased and 17 decreased spots in the total 258 spots in the HFX group compared to CON. Moreover, 12 weeks of VWR showed an increase of 35 and a decrease of 8 spots in a total of 264 paired spots between HFD and HFX. LC-MS/MS of HFD group revealed that proteins involved in ketogenesis, lipid metabolism, and the metabolism of drugs and xenobiotics were upregulated, whereas detoxifying proteins, mitochondrial precursors, transport proteins, proteasomes, and proteins involved in amino acid metabolism were downregulated. On the other hand, VWR counteracted the protein expression profile of HFD-fed mice by upregulating molecular chaperones, gluconeogenesis-, detoxification-, proteasome-, and energy metabolism-related proteins. This study provided a molecular understanding of the HFD- and exercise-induced protein marker expression and presented the beneficial effects of exercise during pathophysiological conditions.
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22
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Influence of Altered Thyroid Hormone Mechanisms in the Progression of Metabolic Dysfunction Associated with Fatty Liver Disease (MAFLD): A Systematic Review. Metabolites 2022; 12:metabo12080675. [PMID: 35893242 PMCID: PMC9330085 DOI: 10.3390/metabo12080675] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 07/15/2022] [Accepted: 07/18/2022] [Indexed: 11/17/2022] Open
Abstract
We performed a systematic review of the mechanisms of thyroid hormones (THs) associated with metabolic dysfunction associated with fatty liver disease (MAFLD). This systematic review was registered under PROSPERO (CRD42022323766). We searched the MEDLINE (via PubMed) and Embase databases from their inception to March 2022. We included studies that assessed thyroid function by measuring the serum level of THs and those involved in MAFLD. We excluded reviews, case reports, editorials, letters, duplicate studies and designed controls. Forty-three studies included MAFLD, eleven analyzed THs, and thirty-two evaluated the mechanisms of THs in MAFLD. Thyroid hormones are essential for healthy growth, development and tissue maintenance. In the liver, THs directly influence the regulation of lipid and carbohydrate metabolism, restoring the homeostatic state of the body. The selected studies showed an association of reduced levels of THs with the development and progression of MAFLD. In parallel, reduced levels of T3 have a negative impact on the activation of co-regulators in the liver, reducing the transcription of genes important in hepatic metabolism. Overall, this is the first review that systematically synthesizes studies focused on the mechanism of THs in the development and progression of MAFLD. The data generated in this systematic review strengthen knowledge of the impact of TH changes on the liver and direct new studies focusing on therapies that use these mechanisms.
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23
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Lluch A, Veiga SR, Latorre J, Moreno-Navarrete JM, Bonifaci N, Nguyen VD, Zhou Y, Horing M, Liebisch G, Olkkonen VM, Llobet-Navas D, Thomas G, Rodriguez-Barrueco R, Fernández-Real JM, Kozma SC, Ortega FJ. A compound directed against S6K1 hampers fat mass expansion and mitigates diet-induced hepatosteatosis. JCI Insight 2022; 7:150461. [PMID: 35737463 PMCID: PMC9431684 DOI: 10.1172/jci.insight.150461] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 06/15/2022] [Indexed: 11/24/2022] Open
Abstract
The ribosomal protein S6 kinase 1 (S6K1) is a relevant effector downstream of the mammalian target of rapamycin complex 1 (mTORC1), best known for its role in the control of lipid homeostasis. Consistent with this, mice lacking the S6k1 gene have a defect in their ability to induce the commitment of fat precursor cells to the adipogenic lineage, which contributes to a significant reduction of fat mass. Here, we assess the therapeutic blockage of S6K1 in diet-induced obese mice challenged with LY2584702 tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumors. We show that diminished S6K1 activity hampers fat mass expansion and ameliorates dyslipidemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver function. Accordingly, decreased mTORC1 signaling in fat (but increased in the liver) segregated with defective epithelial-mesenchymal transition and the impaired expression of Cd36 (coding for a fatty acid translocase) and Lgals1 (Galectin 1) in both tissues. All these factors combined align with reduced adipocyte size and improved lipidomic signatures in the liver, while hepatic steatosis and hypertriglyceridemia were improved in treatments lasting either 3 months or 6 weeks.
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Affiliation(s)
- Aina Lluch
- Department of Diabetes, Endocrinology, and Nutrition (UDEN), Girona Biomedical Research Institute (IDIBGI), Girona, Spain
| | - Sonia R Veiga
- Department of Aging & Metabolism, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Spain
| | - Jèssica Latorre
- Department of Diabetes, Endocrinology, and Nutrition (UDEN), Girona Biomedical Research Institute (IDIBGI), Girona, Spain
| | | | - Núria Bonifaci
- Breast Cancer and Systems Biology Unit, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Spain
| | - Van Dien Nguyen
- Division of Infection and Immunity, Cardiff University School of Medicine, Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom
| | - You Zhou
- Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom
| | - Marcus Horing
- Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
| | - Gerhard Liebisch
- Institute for Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
| | - Vesa M Olkkonen
- Biomedicum, Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - David Llobet-Navas
- Institute of Genetic Medicine, Newcastle University, Newastle, United Kingdom
| | - George Thomas
- Laboratory of Cancer Metabolism, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Spain
| | | | - José M Fernández-Real
- Department of Endocrinology, Girona Biomedical Research Institute (IDIBGI), Girona, Spain
| | - Sara C Kozma
- Laboratory of Cancer Metabolism, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Spain
| | - Francisco J Ortega
- Department of Diabetes, Endocrinology, and Nutrition (UDEN), Girona Biomedical Research Institute (IDIBGI), Girona, Spain
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Zhong M, Yan Y, Yuan H, A R, Xu G, Cai F, Yang Y, Wang Y, Zhang W. Astragalus mongholicus polysaccharides ameliorate hepatic lipid accumulation and inflammation as well as modulate gut microbiota in NAFLD rats. Food Funct 2022; 13:7287-7301. [PMID: 35726797 DOI: 10.1039/d2fo01009g] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatic lipid accumulation, inflammation and gut microbiota dysbiosis are hallmarks of non-alcoholic fatty liver disease (NAFLD), which is the leading cause of chronic liver disease with no therapeutic consensus. The aim of the present study was to elucidate the mechanism of the effects of Astragalus mongholicus polysaccharides (mAPS) on lipid metabolism, inflammation and gut microbiota in a rat model of NAFLD induced by a high-fat diet (HFD). Our results showed that mAPS and Berberine supplementation reduced HFD-induced increases in body weight, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and homeostasis model assessment of insulin resistance (HOMA-IR), and these changes were accompanied by improved histological changes in the liver. Moreover, administration of mAPS and Berberine resulted in lower levels of serum triglycerides, total cholesterol and low-density lipoprotein cholesterol (LDL-c) but higher levels of high-density lipoprotein cholesterol (HDL-c) in HFD-fed rats. mAPS and Berberine treatment markedly reduced HFD-induced hepatic lipid accumulation, which was associated with increased expression of phosphorylated- adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPAR-α) but decreased expression of sterol-regulatory element binding proteins (SREBP-1). Pretreatment with mAPS or Berberine reduced HFD-induced expression of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α). In addition, mAPS downregulated the expression of colonic and hepatic Toll-like receptor 4 (TLR4) as well as phosphorylated- nuclear factor-κB (NF-κB) and nucleotide-binding domain, leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3) but upregulated the expression of zonula occludens-1 (ZO-1) and occludin in HFD-fed rats. Notably, mAPS treatment reshaped the intestinal microbiome by lowering the Firmicutes to Bacteroidetes (F/B) ratio and increasing the abundance of Proteobacteria and Epsilonbacteria. mAPS supplementation had little effect on the profile of fecal short-chain fatty acids (SCFAs), but it significantly decreased the expression of colonic and hepatic G-protein coupled receptor (GPR) 41 and 43. Therefore, mAPS supplementation ameliorates hepatic inflammation and lipid accumulation in NAFLD by modulating the gut microbiota and SCFA-GPR signaling pathways. The present study provides new evidence for mAPS as a natural active substance in the treatment of NAFLD.
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Affiliation(s)
- Mingyue Zhong
- College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, PR China.
| | - Yan Yan
- College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, PR China.
| | - Haisheng Yuan
- College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, PR China.
| | - Rong A
- College of Science, Inner Mongolia Agricultural University, Hohhot, 010018, PR China
| | - Guoquan Xu
- College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, PR China.
| | - Fujuan Cai
- College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, PR China.
| | - Yuning Yang
- College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, PR China.
| | - Yuzhen Wang
- College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, PR China.
| | - Wenguang Zhang
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, 010018, PR China.
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Säll C, Alifrangis L, Dahl K, Friedrichsen MH, Nygård SB, Kristensen K. In vitro CYP450 enzyme down-regulation by GLP-1/glucagon co-agonist does not translate to observed drug-drug interactions in the clinic. Drug Metab Dispos 2022; 50:DMD-AR-2022-000865. [PMID: 35680133 DOI: 10.1124/dmd.122.000865] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/19/2022] [Accepted: 05/05/2022] [Indexed: 12/18/2022] Open
Abstract
NN1177 is a glucagon/glucagon-like peptide 1 receptor co-agonist investigated for chronic weight management and treatment of non-alcoholic steatohepatitis. Here, we show concentration-dependent down-regulation of cytochrome P450 enzymes using freshly isolated human hepatocytes treated with this linear 29-amino acid peptide. Notably, reductions in CYP3A4 mRNA expression (57.2-71.7%) and activity (18.5-51.5%) were observed with a clinically-relevant concentration of 100 nM NN1177. CYP1A2 and CYP2B6 were also affected, but to a lesser extent. Physiological-based pharmacokinetic modelling simulated effects on CYP3A4 and CYP1A2 probe substrates (midazolam and caffeine, respectively) and revealed potential safety concerns related to drug-drug interactions (DDIs). To investigate the clinical relevance of observed in vitro CYP down-regulation, a phase 1 clinical cocktail study was initiated to assess the DDI potential. The study enrolled 45 study participants (BMI 23.0-29.9 kg/m2) to receive a Cooperstown 5+1 cocktail (midazolam, caffeine, omeprazole, dextromethorphan, and S-warfarin/vitamin K) alone and following steady state NN1177 exposure. The analysis of pharmacokinetic profiles for the cocktail drugs showed no significant effect from the co-administration of NN1177 on AUC0-inf for midazolam or S-warfarin. Omeprazole, caffeine, and dextromethorphan generally displayed decreases in AUC0-inf and Cmax following NN1177 co-administration. Thus, the in vitro observations were not reflected in the clinic. These findings highlight remaining challenges associated with standard in vitro systems used to predict DDIs for peptide-based drugs as well as the complexity of DDI trial design for these modalities. Overall, there is an urgent need for better pre-clinical models to assess potential drug-drug interaction risks associated with therapeutic peptides during drug development. Significance Statement This study highlights significant challenges associated with assessing drug-drug interaction risks for therapeutic peptides using in vitro systems, since potential concerns identified by standard assays did not translate to the clinical setting. Further research is required to guide investigators involved in peptide-based drug development towards better non-clinical models in order to more accurately evaluate potential drug-drug interactions.
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Nascè A, Gariani K, Jornayvaz FR, Szanto I. NADPH Oxidases Connecting Fatty Liver Disease, Insulin Resistance and Type 2 Diabetes: Current Knowledge and Therapeutic Outlook. Antioxidants (Basel) 2022; 11:antiox11061131. [PMID: 35740032 PMCID: PMC9219746 DOI: 10.3390/antiox11061131] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/30/2022] [Accepted: 06/03/2022] [Indexed: 12/15/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), characterized by ectopic fat accumulation in hepatocytes, is closely linked to insulin resistance and is the most frequent complication of type 2 diabetes mellitus (T2DM). One of the features connecting NAFLD, insulin resistance and T2DM is cellular oxidative stress. Oxidative stress refers to a redox imbalance due to an inequity between the capacity of production and the elimination of reactive oxygen species (ROS). One of the major cellular ROS sources is NADPH oxidase enzymes (NOX-es). In physiological conditions, NOX-es produce ROS purposefully in a timely and spatially regulated manner and are crucial regulators of various cellular events linked to metabolism, receptor signal transmission, proliferation and apoptosis. In contrast, dysregulated NOX-derived ROS production is related to the onset of diverse pathologies. This review provides a synopsis of current knowledge concerning NOX enzymes as connective elements between NAFLD, insulin resistance and T2DM and weighs their potential relevance as pharmacological targets to alleviate fatty liver disease.
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Affiliation(s)
- Alberto Nascè
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
| | - Karim Gariani
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
- Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland
| | - François R. Jornayvaz
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
- Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Correspondence: (F.R.J.); (I.S.)
| | - Ildiko Szanto
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
- Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland
- Correspondence: (F.R.J.); (I.S.)
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Chi ZC. Metabolic associated fatty liver disease is a disease related to sympathetic nervous system activation. Shijie Huaren Xiaohua Zazhi 2022; 30:465-476. [DOI: 10.11569/wcjd.v30.i11.465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Strong evidence from animal and human studies shows that sympathetic nervous system (SNS) activation is a key factor in the development of metabolic associated fatty liver disease (MAFLD). Activation of the sympathetic nervous system plays an important role in the pathogenesis of obesity, metabolic syndrome, diabetes, hypertension, and MAFLD. When genetically susceptible subjects are exposed to a variety of epigenetic changes, their liver damage may develop into MAFLD. Thus, the pathogenesis of MAFLD is complex, involving the complex interaction of insulin resistance, abnormal hormone secretion, obesity, diet, genetic factors, immune activation, gut microbiota, and other factors. In these processes, the role of sympathetic nerves cannot be underestimated. Notably, SNS has been proposed as a therapeutic target for MAFLD by inhibiting sympathetic nerves. It is worthy of further discussion and research.
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Affiliation(s)
- Zhao-Chun Chi
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
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Huang Y, Wang X, Zhang L, Zheng K, Xiong J, Li J, Cong C, Gong Z, Mao J. Effect of Probiotics Therapy on Nonalcoholic Fatty Liver Disease. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:7888076. [PMID: 35677177 PMCID: PMC9170412 DOI: 10.1155/2022/7888076] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/30/2022] [Accepted: 05/13/2022] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world. The pathogenesis of NAFLD is complex and multifactorial. Clinical studies have shown that alterations in the gut microbiota play a key role in NAFLD. The purpose of this study was to analyze the effect of probiotic supplementation on the treatment of NAFLD patients based on various indicators. METHODS We conducted a meta-analysis investigating the relationship between NAFLD and probiotic supplementation. Embase, PubMed, and Web of Science databases were searched by computer, and then, eligible studies were identified. Finally, a total of high-quality randomized controlled trials were selected involving 1403 participants. Meta-analysis was performed using the RevMan 5.3 software which was systematically searched for works published through Dec. 1, 2021, in the present study. RESULTS The meta-analysis results showed that the probiotics supplementation improved hepatocyte injury and significantly reduced the level of ALT (P = 0.00001), AST (P = 0.0009), GGT (P = 0.04), TG (P = 0.01), LDL-C (P = 0.0005), HDL-C (P = 0.0002), insulin (P = 0.003), IR (P = 0.03), BMI (P = 0.03), TNF-α (P = 0.03), and CRP (P = 0.02), respectively, in NAFLD patients. CONCLUSION The present study suggests that probiotics therapy may improve liver enzyme levels, regulated lipid metabolism, reduced insulin resistance, and improved inflammation in NAFLD patients. It supports the potential role of probiotics supplementation in the treatment of NAFLD.
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Affiliation(s)
- Yuanshe Huang
- Anshun University, Guizhou, Anshun 561000, China
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Xiaodong Wang
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China
| | - Lai Zhang
- Anshun University, Guizhou, Anshun 561000, China
| | - Ke Zheng
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China
| | - Jie Xiong
- Department of Pharmacy, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders/Chongqing Key Laboratory of Pediatrics/Children's Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Jing Li
- Anshun University, Guizhou, Anshun 561000, China
| | - Chunlei Cong
- Anshun University, Guizhou, Anshun 561000, China
| | - Zhaomiao Gong
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China
| | - Jingxin Mao
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China
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Kothari V, Babu JR, Mathews ST. AMP activated kinase negatively regulates hepatic Fetuin-A via p38 MAPK-C/EBPβ/E3 Ubiquitin Ligase Signaling pathway. PLoS One 2022; 17:e0266472. [PMID: 35522655 PMCID: PMC9075660 DOI: 10.1371/journal.pone.0266472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 03/21/2022] [Indexed: 11/29/2022] Open
Abstract
Fetuin-A (Fet-A) is a liver-secreted phosphorylated protein, known to impair insulin signaling, which has been shown to be associated with obesity, insulin resistance, and incident diabetes. Fet-A interacts with the insulin-stimulated insulin receptor (IR) and inhibits IR tyrosine kinase activity and glucose uptake. It has been shown that high glucose increases Fet-A expression through the ERK1/2 signaling pathway. However, factors that downregulate Fet-A expression and their potential mechanisms are unclear. We examined the effect of AMP-activated protein kinase (AMPK) on high-glucose induced Fet-A expression in HepG2 cells, Hep3B cells and primary rat hepatocytes. High glucose increased Fet-A and phosphorylated (Ser312) fetuin-A (pFet-A) expression, which are known to impair insulin signaling. AICAR-induced AMPK activation significantly down-regulated high glucose-induced Fet-A expression and secretion of pFet-A while treatment with Compound C (AMPK inhibitor), SB202190 (p38 MAPK inhibitor) or p38 MAPK siRNA transfection prevented AICAR-induced downregulation of Fet-A expression. In addition, activation of p38 MAPK, by anisomycin, decreased the hepatic expression of Fet-A. Further, we our studies have shown that short-term effect of AICAR-treatment on Fet-A expression was mediated by proteosomal degradation, and long-term treatment of AICAR was associated with decrease in hepatic expression of C/EBP beta, an important transcription factor involved in the regulation of Fet-A. Taken together, our studies implicate a critical role for AMPK-p38 MAPK-C/EBPb-ubiquitin-proteosomal axis in the regulation of the expression of hepatic Fet-A.
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Affiliation(s)
- Vishal Kothari
- Department of Nutrition and Dietetics, Boshell Diabetes and Metabolic Diseases Research Program, Auburn University, Auburn, AL, United States of America
| | - Jeganathan Ramesh Babu
- Department of Nutrition and Dietetics, Boshell Diabetes and Metabolic Diseases Research Program, Auburn University, Auburn, AL, United States of America
| | - Suresh T. Mathews
- Department of Nutrition and Dietetics, Boshell Diabetes and Metabolic Diseases Research Program, Auburn University, Auburn, AL, United States of America
- Department of Nutrition and Dietetics, Samford University, Birmingham, AL, United States of America
- * E-mail:
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Velázquez AM, Bentanachs R, Sala‐Vila A, Lázaro I, Rodríguez‐Morató J, Sánchez RM, Alegret M, Roglans N, Laguna JC. ChREBP-driven DNL and PNPLA3 Expression Induced by Liquid Fructose are Essential in the Production of Fatty Liver and Hypertriglyceridemia in a High-Fat Diet-Fed Rat Model. Mol Nutr Food Res 2022; 66:e2101115. [PMID: 35124887 PMCID: PMC9286604 DOI: 10.1002/mnfr.202101115] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/18/2022] [Indexed: 11/25/2022]
Abstract
SCOPE The aim of this study is to delineate the contribution of dietary saturated fatty acids (FA) versus liquid fructose to fatty liver and hypertriglyceridemia. METHODS AND RESULTS Three groups of female rats are maintained for 3 months in standard chow (CT); High-fat diet (46.9% of fat-derived calories, rich in palmitic and stearic FA, HFD); and HFD with 10% w/v fructose in drinking water (HFHFr). Zoometric parameters, plasma biochemistry, and liver Oil-Red O (ORO) staining, lipidomics, and expression of proteins involved in FA metabolism are analyzed. Both diets increase ingested calories without modifying body weight. Only the HFHFr diet increases liver triglycerides (x11.0), with hypertriglyceridemia (x1.7) and reduces FA β-oxidation (x0.7), and increases liver FA markers of DNL (de novo lipogenesis). Whereas HFD livers show a high content of ceramides, HFHFr samples show unchanged ceramides, and an increase in diacylglycerols. Only the HFHFr diet leads to a marked increase in the expression of enzymes involved in DNL and triglyceride metabolism, such as carbohydrate response element binding protein β (ChREBPβ, x3.2), a transcription factor that regulates DNL, and patatin-like phospholipase domain-containing 3 (PNPLA3, x2.6), a lipase that mobilizes stored triglycerides for VLDL secretion. CONCLUSION The addition of liquid-fructose to dietary FA is determinant in liver steatosis and hypertriglyceridemia production, through increased DNL and PNPLA3 expression, and reduced FA catabolism.
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Affiliation(s)
- Ana Magdalena Velázquez
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food ScienceUniversity of BarcelonaAvda Joan XXIII 27–31Barcelona08028Spain
| | - Roger Bentanachs
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food ScienceUniversity of BarcelonaAvda Joan XXIII 27–31Barcelona08028Spain
| | - Aleix Sala‐Vila
- IMIM‐Hospital del Mar Medical Research InstituteBarcelona08003Spain
- Barcelonaβeta Brain Research CenterPasqual Maragall FoundationBarcelona08005Spain
| | - Iolanda Lázaro
- IMIM‐Hospital del Mar Medical Research InstituteBarcelona08003Spain
| | - Jose Rodríguez‐Morató
- Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN)Instituto de Salud Carlos III (ISCIII)Madrid28029Spain
- IMIM‐Hospital del Mar Medical Research InstituteBarcelona08003Spain
- Department of Experimental and Health SciencesUniversitat Pompeu Fabra (CEXS‐UPF)Barcelona08003Spain
| | - Rosa M. Sánchez
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food ScienceUniversity of BarcelonaAvda Joan XXIII 27–31Barcelona08028Spain
- Institute of BiomedicineUniversity of BarcelonaBarcelona08028Spain
- Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN)Instituto de Salud Carlos III (ISCIII)Madrid28029Spain
| | - Marta Alegret
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food ScienceUniversity of BarcelonaAvda Joan XXIII 27–31Barcelona08028Spain
- Institute of BiomedicineUniversity of BarcelonaBarcelona08028Spain
- Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN)Instituto de Salud Carlos III (ISCIII)Madrid28029Spain
| | - Núria Roglans
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food ScienceUniversity of BarcelonaAvda Joan XXIII 27–31Barcelona08028Spain
- Institute of BiomedicineUniversity of BarcelonaBarcelona08028Spain
- Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN)Instituto de Salud Carlos III (ISCIII)Madrid28029Spain
| | - Juan Carlos Laguna
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food ScienceUniversity of BarcelonaAvda Joan XXIII 27–31Barcelona08028Spain
- Institute of BiomedicineUniversity of BarcelonaBarcelona08028Spain
- Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN)Instituto de Salud Carlos III (ISCIII)Madrid28029Spain
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Yardeni D, Toledano R, Novack V, Shalev A, Wolak A, Rotman Y, Etzion O. The Association of Alanine Aminotransferase Levels With Myocardial Perfusion Imaging and Cardiovascular Morbidity. J Cardiovasc Pharmacol Ther 2022; 27:10742484221074585. [PMID: 35077243 PMCID: PMC8840806 DOI: 10.1177/10742484221074585] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Studies suggest that non-alcoholic fatty liver disease (NAFLD) is associated with an independent risk of cardiovascular disease (CVD). We utilized a large cohort of patients undergoing myocardial perfusion imaging (MPI) with single photon emission computed tomography (SPECT) to determine the association between alanine aminotransferase (ALT) as a surrogate marker for presumed NAFLD, and the presence of myocardial ischemia and mortality. METHODS We retrospectively assessed SPECT-MPI results and medical records of individuals evaluated between 1997 and 2008. We excluded patients with known non-NAFLD liver diseases, ALT values <17 or >340 U/L and absent liver tests. Elevated ALT cases were classified as presumed NAFLD. The primary endpoint was abnormal SPECT-MPI. Secondary endpoints included cardiac death, acute myocardial infarction and all-cause mortality. RESULTS Of 26,034 patients who underwent SPECT-MPI, 11,324 met inclusion criteria. 1635 (14.4%) patients had elevated ALT. SPECT-MPI results did not differ significantly between subjects with elevated ALT and controls. Elevated ALT was associated with increased risk for the composite endpoint of cardiac death or acute myocardial infarction at 5-year follow-up (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.01-1.67) and in all-cause mortality (HR 1.27, CI 1.02-1.58) but only in patients with normal SPECT-MPI. CONCLUSIONS The long-term mortality of patients with abnormal SPECT-MPI is not modulated by ALT, likely reflecting an already high risk and established CVD. However, patients with normal SPECT-MPI are at increased risk for a future cardiac event if they have an elevated ALT level, suggesting an important role for NAFLD in earlier stages of CVD.
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Affiliation(s)
- David Yardeni
- Department of Gastroenterology and Liver Diseases, Soroka University Medical Center, Beer-Sheva, Israel
| | - Ronen Toledano
- Clinical Research Center, Soroka University Medical Center, Beer-Sheva, Israel
| | - Victor Novack
- Clinical Research Center, Soroka University Medical Center, Beer-Sheva, Israel
| | - Aryeh Shalev
- Cardiology Department, Soroka University Medical Center, Beer-Sheva, Israel
| | - Arik Wolak
- Cardiology Department, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Yaron Rotman
- Liver & Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Ohad Etzion
- Department of Gastroenterology and Liver Diseases, Soroka University Medical Center, Beer-Sheva, Israel
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Zhou Z, Zhang J, You L, Wang T, Wang K, Wang L, Kong X, Gao Y, Sun X. Application of herbs and active ingredients ameliorate non-alcoholic fatty liver disease under the guidance of traditional Chinese medicine. Front Endocrinol (Lausanne) 2022; 13:1000727. [PMID: 36204095 PMCID: PMC9530134 DOI: 10.3389/fendo.2022.1000727] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 08/29/2022] [Indexed: 11/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a global health problem, and its prevalence has been on the rise in recent years. Traditional Chinese Medicine (TCM) contains a wealth of therapeutic resources and has been in use for thousands of years regarding the prevention of liver disease and has been shown to be effective in the treatment of NAFLD in China. but the molecular mechanisms behind it have not been elucidated. In this article, we have updated and summarized the research and evidence concerning herbs and their active ingredients for the treatment in vivo and vitro models of NAFLD or NASH, by searching PubMed, Web of Science and SciFinder databases. In particular, we have found that most of the herbs and active ingredients reported so far have the effect of clearing heat and dispelling dampness, which is consistent with the concept of dampness-heat syndrome, in TCM theory. we have attempted to establish the TCM theory and modern pharmacological mechanisms links between herbs and monomers according to their TCM efficacy, experiment models, targets of modulation and amelioration of NAFLD pathology. Thus, we provide ideas and perspectives for further exploration of the pathogenesis of NAFLD and herbal therapy, helping to further the scientific connotation of TCM theories and promote the modernization of TCM.
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Affiliation(s)
- Zhijia Zhou
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jinghao Zhang
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Liping You
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Wang
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kaixia Wang
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Infection, Oriental Hospital Affiliated to Tongji University, Shanghai, China
| | - Lingtai Wang
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoni Kong
- Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Xiaoni Kong, ; Yueqiu Gao, ; Xuehua Sun,
| | - Yueqiu Gao
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Xiaoni Kong, ; Yueqiu Gao, ; Xuehua Sun,
| | - Xuehua Sun
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Xiaoni Kong, ; Yueqiu Gao, ; Xuehua Sun,
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Garbuzenko DV, Belov DV. Non-alcoholic fatty liver disease as an independent factor of cardiometabolic risk of cardiovascular diseases. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2021. [DOI: 10.31146/1682-8658-ecg-194-10-22-34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a pressing public health problem affecting up to a third of the world's adult population. The main reasons for its high mortality rate are cardiovascular diseases. They are caused by subclinical atherosclerosis characteristic of NAFLD, venous thromboembolic complications, functional and structural myocardial disorders, calcification of heart valves, heart rhythm and conduction disturbances. At the same time, NAFLD can serve as an independent factor of the cardiometabolic risk of their development, which is associated with atherogenic dyslipidemia, as well as the release of numerous pro-inflammatory mediators both from the pathologically altered liver and as a result of systemic endotoxemia, which is the result of disturbance of the intestinal microbiota, accompanied by a decrease in intestinal microbial gene richness., a change in its composition and function, followed by bacterial translocation. Considering that most patients with NAFLD die from cardiovascular complications, it becomes obvious that exclusively “liver-oriented” principles of their treatment cannot be sufficient, but require a multidisciplinary team approach involving cardiologists, cardiac surgeons and doctors of other related specialties.
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von Loeffelholz C, Roth J, Coldewey SM, Birkenfeld AL. The Role of Physical Activity in Nonalcoholic and Metabolic Dysfunction Associated Fatty Liver Disease. Biomedicines 2021; 9:biomedicines9121853. [PMID: 34944668 PMCID: PMC8698784 DOI: 10.3390/biomedicines9121853] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/01/2021] [Accepted: 12/02/2021] [Indexed: 12/17/2022] Open
Abstract
Sedentary behavior constitutes a pandemic health threat contributing to the pathophysiology of obesity and type 2 diabetes (T2D). Sedentarism is further associated with liver disease and particularly with nonalcoholic/metabolic dysfunction associated fatty liver disease (NAFLD/MAFLD). Insulin resistance (IR) represents an early pathophysiologic key element of NAFLD/MAFLD, prediabetes and T2D. Current treatment guidelines recommend regular physical activity. There is evidence, that physical exercise has impact on a variety of molecular pathways, such as AMP-activated protein kinase and insulin signaling as well as glucose transporter 4 translocation, modulating insulin action, cellular substrate flow and in particular ectopic lipid and glycogen storage in a positive manner. Therefore, physical exercise can lead to substantial clinical benefit in persons with diabetes and/or NAFLD/MAFLD. However, experience from long term observational studies shows that the patients’ motivation to exercise regularly appears to be a major limitation. Strategies to integrate everyday physical activity (i.e., nonexercise activity thermogenesis) in lifestyle treatment schedules might be a promising approach. This review aggregates evidence on the impact of regular physical activity on selected molecular mechanisms as well as clinical outcomes of patients suffering from IR and NAFLD/MAFLD.
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Affiliation(s)
- Christian von Loeffelholz
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07747 Jena, Germany; (J.R.); (S.M.C.)
- Correspondence: ; Tel.: +49-3641-9323-177; Fax: +49-3641-9323-102
| | - Johannes Roth
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07747 Jena, Germany; (J.R.); (S.M.C.)
| | - Sina M. Coldewey
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07747 Jena, Germany; (J.R.); (S.M.C.)
- Septomics Research Center, Jena University Hospital, 07747 Jena, Germany
- Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany
| | - Andreas L. Birkenfeld
- Department of Diabetology Endocrinology and Nephrology, Internal Medicine IV, University Hospital Tübingen, Eberhard Karls University Tübingen, 72074 Tübingen, Germany;
- Division of Translational Diabetology, Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Eberhard Karls University Tübingen, 72074 Tübingen, Germany
- Department of Diabetes, School of Life Course Science and Medicine, Kings College London, London WC2R 2LS, UK
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Yu X, Chen C, Guo Y, Tong Y, Zhao Y, Wu L, Sun X, Wu X, Song Z. High NAFLD fibrosis score in non-alcoholic fatty liver disease as a predictor of carotid plaque development: a retrospective cohort study based on regular health check-up data in China. Ann Med 2021; 53:1621-1631. [PMID: 34498502 PMCID: PMC8439219 DOI: 10.1080/07853890.2021.1974081] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 08/23/2021] [Indexed: 10/31/2022] Open
Abstract
PURPOSES There is increasing concern regarding cardiovascular risk in non-alcoholic fatty liver disease (NAFLD) patients with liver fibrosis. This study aims: (1) to assess the association between NAFLD and liver fibrosis status and the development of carotid plaque (CP), and (2) to identify CP risk factors among general population with different baseline NAFLD and liver fibrosis status. METHODS This retrospective cohort study included 14,288 adult participants who went for regular health check-ups between 2014 and 2019, in one hospital in Zhejiang, China. NAFLD was diagnosed by abdominal ultrasound and the NAFLD fibrosis score (NFS) was calculated to reflect the extent of liver fibrosis. Cox proportional hazards analyses were applied to assess the risk of CP development across groups with different baseline NAFLD and NFS status. RESULTS NAFLD participants with high NFS had higher risk of CP compared to non-NAFLD participants (adjusted hazard ratio 1.68, 95% confidence interval [CI] 1.43-1.96, p < .001). Progression from NAFLD free and NAFLD with low NFS to NAFLD with high NFS are associated with 1.56-fold (95% CI 1.21-2.01, p = .001) and 1.43-fold (95% CI 1.11-1.84, p = .006) increased risk of CP, respectively. Risk factors associated with CP vary based on baseline NAFLD and NFS status. Among NAFLD participants with high NFS, hypertension is the only significant risk factor after adjustment for other potential influencing factors. CONCLUSIONS NAFLD and liver fibrosis status can be an independent predictor for CP development regardless of metabolic abnormalities. Hypertension is a major risk factor for CP development among NAFLD patients with high NFS.KEY MESSAGESNon-alcoholic fatty liver disease (NAFLD) and liver fibrosis status can be an independent predictor for development of carotid plaque.Progression from NAFLD free and NAFLD with low NAFLD fibrosis score (NFS) to NAFLD with high NFS are associated with increased risk of carotid plaque.Risk factors associated with carotid plaque vary based on baseline NAFLD and NFS status, and hypertension plays the most important role among patients with NAFLD and high NFS.
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Affiliation(s)
- Xinyan Yu
- Department of General Practice and Health Management Center, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chen Chen
- Department of Big Data in Health Science, School of Public Health, Zhejiang University, Hangzhou, China
- Center for Biostatistics, Bioinformatics, and Big Data, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yi Guo
- Department of General Practice and Health Management Center, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yuling Tong
- Department of General Practice and Health Management Center, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yi Zhao
- Department of General Practice and Health Management Center, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lingyan Wu
- Department of General Practice and Health Management Center, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xue Sun
- Department of General Practice and Health Management Center, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xifeng Wu
- Department of Big Data in Health Science, School of Public Health, Zhejiang University, Hangzhou, China
- Center for Biostatistics, Bioinformatics, and Big Data, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhenya Song
- Department of General Practice and Health Management Center, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Liu X, Sun R, Li Z, Xiao R, Lv P, Sun X, Olson MA, Gong Y. Luteolin alleviates non-alcoholic fatty liver disease in rats via restoration of intestinal mucosal barrier damage and microbiota imbalance involving in gut-liver axis. Arch Biochem Biophys 2021; 711:109019. [PMID: 34478730 DOI: 10.1016/j.abb.2021.109019] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/19/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is demonstrated to be closely related to the disorder of gut microbiota and the intestinal mucosal barrier. Luteolin is a natural flavonoid with various activities. We aimed to investigate whether Luteolin can alleviate NAFLD and its possible mechanism involving the gut-liver axis. A rat NAFLD model was established by feeding a high-fat diet (HFD), and Luteolin was administered intragastrically. The effects of Luteolin on liver biochemical parameters, intestinal histopathology and integrity, gut microbiota, lipopolysaccharides (LPS), inflammatory cytokines, and the Toll-like receptor 4 (TLR4) signaling pathway were evaluated. We found that Luteolin restored the expression of the tight junction proteins in the intestine and ameliorated the increase permeability of the intestinal mucosa to Fluorescein isothiocyanate-dextran (FD4) caused by a high-fat diet, thus enhancing the function of the intestinal barrier. In addition, Luteolin inhibited the TLR4 signaling pathway in the liver, thereby reducing the secretion of pro-inflammatory factors and alleviating NAFLD. 16S rRNA gene sequencing revealed that Luteolin intervention significantly altered the composition of the gut microbiota in NAFLD rats and increased the richness of gut microbiota. Luteolin alleviates NAFLD in rats via restoration and repair of the damaged intestinal mucosal barrier and microbiota imbalance.
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Affiliation(s)
- Xia Liu
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong, China
| | - Runzhou Sun
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong, China
| | - Zhaozhen Li
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong, China
| | - Ruixin Xiao
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong, China
| | - Pengfei Lv
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong, China
| | - Xiangrong Sun
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Mark A Olson
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China; Department of Chemistry, Northwestern University, Evanston, IL, USA
| | - Yanling Gong
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong, China.
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The Interplay between Insulin Resistance, Inflammation, Oxidative Stress, Base Excision Repair and Metabolic Syndrome in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2021; 22:ijms222011128. [PMID: 34681787 PMCID: PMC8537238 DOI: 10.3390/ijms222011128] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 02/06/2023] Open
Abstract
One of the most common chronic liver disorders, affecting mainly people in Western countries, is nonalcoholic fatty liver disease (NAFLD). Unfortunately, its pathophysiological mechanism is not fully understood, and no dedicated treatment is available. Simple steatosis can lead to nonalcoholic steatohepatitis and even to fibrosis, cancer, and cirrhosis of the liver. NAFLD very often occurs in parallel with type 2 diabetes mellitus and in obese people. Furthermore, it is much more likely to develop in patients with metabolic syndrome (MS), whose criteria include abdominal obesity, elevated blood triacylglycerol level, reduced high-density lipoprotein cholesterol level, increased blood pressure, and high fasting glucose. An important phenomenon in MS is also insulin resistance (IR), which is very common in NAFLD. Liver IR and NAFLD development are linked through an interaction between the accumulation of free fatty acids, hepatic inflammation, and increased oxidative stress. The liver is particularly exposed to elevated levels of reactive oxygen species due to a large number of mitochondria in hepatocytes. In these organelles, the main DNA repair pathway is base excision repair (BER). The present article will illustrate how impairment of BER may be related to the development of NAFLD.
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Wu J, Zhang F, Ruan H, Chang X, Wang J, Li Z, Jin W, Shi Y. Integrating Network Pharmacology and RT-qPCR Analysis to Investigate the Mechanisms Underlying ZeXie Decoction-Mediated Treatment of Non-alcoholic Fatty Liver Disease. Front Pharmacol 2021; 12:722016. [PMID: 34566646 PMCID: PMC8458890 DOI: 10.3389/fphar.2021.722016] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/26/2021] [Indexed: 01/14/2023] Open
Abstract
ZeXie Decoction (ZXD) is a traditional Chinese medicine composed of Alisma orientalis (Sam.) Juzep. and Atractylodes macrocephala Koidz. ZXD has been widely used to treat non-alcoholic fatty liver disease (NAFLD). The mechanistic basis for the pharmacological activity of ZXD, however, remains poorly understood. In this study, we used a network pharmacology approach and investigated the association between ZXD and NAFLD. We identified the active ingredients of ZXD and screened the potential targets of these ingredients, after which a database of relevant NAFLD-related targets were constructed and several enrichment analyses were performed. Furthermore, the ethanol and aqueous extracts of ZXD were prepared and experimental pharmacology validation was conducted using RT-qPCR of the non-alcoholic fatty liver disease (NAFLD) model in Sprague-Dawley (SD) rats. As a result, a herb-compound-target-pathway network model was developed, and HMGCR, SREBP-2, MAPK1, and NF-κBp65 targets were validated. The gene expression results of these four targets were consistent with those of the network pharmacology prediction. Using an integration strategy, we revealed that ZXD could treat NAFLD by targeting HMGCR, SREBP-2, MAPK1, and NF-κBp65.
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Affiliation(s)
- Jiashuo Wu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fangqing Zhang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haonan Ruan
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoyan Chang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jingxun Wang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhuangzhuang Li
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weiyi Jin
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,College of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Yue Shi
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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von Loeffelholz C, Coldewey SM, Birkenfeld AL. A Narrative Review on the Role of AMPK on De Novo Lipogenesis in Non-Alcoholic Fatty Liver Disease: Evidence from Human Studies. Cells 2021; 10:cells10071822. [PMID: 34359991 PMCID: PMC8306246 DOI: 10.3390/cells10071822] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/01/2021] [Accepted: 07/15/2021] [Indexed: 02/06/2023] Open
Abstract
5′AMP-activated protein kinase (AMPK) is known as metabolic sensor in mammalian cells that becomes activated by an increasing adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio. The heterotrimeric AMPK protein comprises three subunits, each of which has multiple phosphorylation sites, playing an important role in the regulation of essential molecular pathways. By phosphorylation of downstream proteins and modulation of gene transcription AMPK functions as a master switch of energy homeostasis in tissues with high metabolic turnover, such as the liver, skeletal muscle, and adipose tissue. Regulation of AMPK under conditions of chronic caloric oversupply emerged as substantial research target to get deeper insight into the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Evidence supporting the role of AMPK in NAFLD is mainly derived from preclinical cell culture and animal studies. Dysbalanced de novo lipogenesis has been identified as one of the key processes in NAFLD pathogenesis. Thus, the scope of this review is to provide an integrative overview of evidence, in particular from clinical studies and human samples, on the role of AMPK in the regulation of primarily de novo lipogenesis in human NAFLD.
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Affiliation(s)
- Christian von Loeffelholz
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07747 Jena, Germany;
- Correspondence: ; Tel.: +49-3641-9323-177; Fax: +49-3641-9323-102
| | - Sina M. Coldewey
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07747 Jena, Germany;
- Septomics Research Center, Jena University Hospital, 07747 Jena, Germany
- Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany
| | - Andreas L. Birkenfeld
- Department of Diabetology Endocrinology and Nephrology, University Hospital Tübingen, Eberhard Karls University Tübingen, 72074 Tübingen, Germany;
- Department of Therapy of Diabetes, Institute of Diabetes Research and Metabolic Diseases in the Helmholtz Center Munich, Eberhard Karls University Tübingen, 72074 Tübingen, Germany
- Division of Diabetes and Nutritional Sciences, Rayne Institute, King’s College London, London SE5 9RJ, UK
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González-Arceo M, Gómez-Zorita S, Aguirre L, Portillo MP. Effect of Microalgae and Macroalgae Extracts on Non-Alcoholic Fatty Liver Disease. Nutrients 2021; 13:2017. [PMID: 34208211 PMCID: PMC8230871 DOI: 10.3390/nu13062017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 12/05/2022] Open
Abstract
The present review aims to gather scientific evidence regarding the beneficial effects of microalgae and macroalgae extracts on non-alcoholic fatty liver disease (NAFLD). The described data show that both microalgae and macroalgae improved this alteration. The majority of the reported studies analysed the preventive effects because algae were administered to animals concurrent with the diet that induced NAFLD. The positive effects were demonstrated using a wide range of doses, from 7.5 to 300 mg/kg body weight/day or from 1 to 10% in the diet, and experimental periods ranged from 3 to 16 weeks. Two important limitations on the scientific knowledge available to date are that very few studies have researched the mechanisms of action underlying the preventive effects of microalgae on NAFLD and that, for the majority of the algae studied, a single paper has been reported. For these reasons, it is not possible to establish the best conditions in order to know the beneficial effects that these algae could bring. In this scenario, further studies are needed. Moreover, the beneficial effects of algae observed in rodent need to be confirmed in humans before we can start considering these products as new tools in the fight against fatty liver disease.
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Affiliation(s)
- Maitane González-Arceo
- Nutrition and Obesity Group, Department of Pharmacy and Food Science, Faculty of Pharmacy and Lucio Lascaray Research Center, University of the Basque Country (UPV/EHU), 01008 Vitoria-Gasteiz, Spain; (M.G.-A.); (M.P.P.)
| | - Saioa Gómez-Zorita
- Nutrition and Obesity Group, Department of Pharmacy and Food Science, Faculty of Pharmacy and Lucio Lascaray Research Center, University of the Basque Country (UPV/EHU), 01008 Vitoria-Gasteiz, Spain; (M.G.-A.); (M.P.P.)
- Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), 28222 Madrid, Spain
| | - Leixuri Aguirre
- Nutrition and Obesity Group, Department of Pharmacy and Food Science, Faculty of Pharmacy and Lucio Lascaray Research Center, University of the Basque Country (UPV/EHU), 01008 Vitoria-Gasteiz, Spain; (M.G.-A.); (M.P.P.)
- Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), 28222 Madrid, Spain
| | - María P. Portillo
- Nutrition and Obesity Group, Department of Pharmacy and Food Science, Faculty of Pharmacy and Lucio Lascaray Research Center, University of the Basque Country (UPV/EHU), 01008 Vitoria-Gasteiz, Spain; (M.G.-A.); (M.P.P.)
- Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), 28222 Madrid, Spain
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Li H, Xu Q, Xu C, Hu Y, Yu X, Zhao K, Li M, Li M, Xu J, Kuang H. Bicyclol Regulates Hepatic Gluconeogenesis in Rats with Type 2 Diabetes and Non-alcoholic Fatty Liver Disease by Inhibiting Inflammation. Front Pharmacol 2021; 12:644129. [PMID: 34093184 PMCID: PMC8175979 DOI: 10.3389/fphar.2021.644129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 05/04/2021] [Indexed: 12/30/2022] Open
Abstract
Hepatic gluconeogenesis plays an important role in maintaining the body’s glucose metabolism homeostasis. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases, when combined with type 2 diabetes mellitus (T2DM), it can cause severe glucose metabolism disorders. Studies have confirmed that chronic liver inflammatory lesions are the basis of T2DM combined with NAFLD (T2DM–NAFLD), inhibiting liver inflammation can improve glucose metabolism disorders. It is essential to explore safe and effective drugs to inhibit liver inflammation to improve the body’s glucose metabolism disorders. Bicyclol is a biphenyl derivative that has anti-oxidative and anti-inflammatory properties. In the present study, the hepatoprotective effects and underlying mechanisms of bicyclol in T2DM–NAFLD were investigated, and T2DM–NAFLD with/without bicyclol treatment models were established. The results revealed that bicyclol alleviated fasting blood glucose, serum transaminase levels, insulin resistance, hepatic adipogenesis, lipid accumulation and markedly reduced T2DM–NAFLD rat histological alterations of livers. Not only that, bicyclol markedly attenuated T2DM–NAFLD induced production of inflammation factors (IL-1β and TNF-α). Moreover, bicyclol suppressed the expression of insulin/gluconeogenesis signaling pathway (Akt, PGC-1α and PEPCK). These findings suggested that bicyclol might be a potentially effective drug for the treatment of T2DM–NAFLD and other metabolic disorders.
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Affiliation(s)
- Hongxue Li
- First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qian Xu
- First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chengye Xu
- First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yuxin Hu
- First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xingyang Yu
- First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Kangqi Zhao
- First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Mingqing Li
- First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Meng Li
- First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Junfang Xu
- First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongyu Kuang
- First Affiliated Hospital of Harbin Medical University, Harbin, China
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Jones RB, Arenaza L, Rios C, Plows JF, Berger PK, Alderete TL, Fogel JL, Nayak K, Mohamed P, Hwang D, Palmer S, Sinatra F, Allayee H, Kohli R, Goran MI. PNPLA3 Genotype, Arachidonic Acid Intake, and Unsaturated Fat Intake Influences Liver Fibrosis in Hispanic Youth with Obesity. Nutrients 2021; 13:1621. [PMID: 34065978 PMCID: PMC8151324 DOI: 10.3390/nu13051621] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/05/2021] [Accepted: 05/08/2021] [Indexed: 01/03/2023] Open
Abstract
Non-alcoholic fatty liver disease impacts 15.2% of Hispanic adolescents and can progress to a build-up of scared tissue called liver fibrosis. If diagnosed early, liver fibrosis may be reversible, so it is necessary to understand risk factors. The aims of this study in 59 Hispanic adolescents with obesity were to: (1) identify potential biological predictors of liver fibrosis and dietary components that influence liver fibrosis, and (2) determine if the association between dietary components and liver fibrosis differs by PNPLA3 genotype, which is highly prevalent in Hispanic adolescents and associated with elevated liver fat. We examined liver fat and fibrosis, genotyped for PNPLA3 gene, and assessed diet via 24-h diet recalls. The prevalence of increased fibrosis was 20.9% greater in males, whereas participants with the GG genotype showed 23.7% greater prevalence. Arachidonic acid was associated with liver fibrosis after accounting for sex, genotype, and liver fat (β = 0.072, p = 0.033). Intakes of several dietary types of unsaturated fat have different associations with liver fibrosis by PNPLA3 genotype after accounting for sex, caloric intake, and liver fat. These included monounsaturated fat (βCC/CG = -0.0007, βGG = 0.03, p-value = 0.004), polyunsaturated fat (βCC/CG = -0.01, βGG = 0.02, p-value = 0.01), and omega-6 (βCC/CG = -0.0102, βGG = 0.028, p-value = 0.01). Results from this study suggest that reduction of arachidonic acid and polyunsaturated fatty acid intake might be important for the prevention of non-alcoholic fatty liver disease progression, especially among those with PNPLA3 risk alleles.
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Affiliation(s)
- Roshonda B. Jones
- Department of Pediatrics, The Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA; (R.B.J.); (C.R.); (J.F.P.); (P.K.B.); (J.L.F.); (F.S.); (R.K.)
| | - Lide Arenaza
- Institute for Innovation and Sustainable Development in Food Chain (IS-FOOD), Public University of Navarra, 31009 Pamplona, Spain;
| | - Claudia Rios
- Department of Pediatrics, The Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA; (R.B.J.); (C.R.); (J.F.P.); (P.K.B.); (J.L.F.); (F.S.); (R.K.)
| | - Jasmine F. Plows
- Department of Pediatrics, The Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA; (R.B.J.); (C.R.); (J.F.P.); (P.K.B.); (J.L.F.); (F.S.); (R.K.)
| | - Paige K. Berger
- Department of Pediatrics, The Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA; (R.B.J.); (C.R.); (J.F.P.); (P.K.B.); (J.L.F.); (F.S.); (R.K.)
| | - Tanya L. Alderete
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA;
| | - Jennifer L. Fogel
- Department of Pediatrics, The Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA; (R.B.J.); (C.R.); (J.F.P.); (P.K.B.); (J.L.F.); (F.S.); (R.K.)
| | - Krishna Nayak
- Ming Hsieh Department of Electrical and Computer Engineering, University of Southern California, Los Angeles, CA 90007, USA;
| | - Passant Mohamed
- Department of Radiology, University of Southern California, Los Angeles, CA 90033, USA; (P.M.); (D.H.); (S.P.)
| | - Darryl Hwang
- Department of Radiology, University of Southern California, Los Angeles, CA 90033, USA; (P.M.); (D.H.); (S.P.)
| | - Suzanne Palmer
- Department of Radiology, University of Southern California, Los Angeles, CA 90033, USA; (P.M.); (D.H.); (S.P.)
| | - Frank Sinatra
- Department of Pediatrics, The Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA; (R.B.J.); (C.R.); (J.F.P.); (P.K.B.); (J.L.F.); (F.S.); (R.K.)
| | - Hooman Allayee
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA;
| | - Rohit Kohli
- Department of Pediatrics, The Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA; (R.B.J.); (C.R.); (J.F.P.); (P.K.B.); (J.L.F.); (F.S.); (R.K.)
| | - Michael I. Goran
- Department of Pediatrics, The Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA; (R.B.J.); (C.R.); (J.F.P.); (P.K.B.); (J.L.F.); (F.S.); (R.K.)
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The Impact of the NLRP3 Pathway in the Pathogenesis of Non-Alcoholic Fatty Liver Disease and Alcohol-Related Liver Disease. LIVERS 2021. [DOI: 10.3390/livers1020007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The presence of hepatic steatosis and inflammation is increasingly associated with both metabolic and alcohol-related liver conditions. Both are on the increase globally and, apart from liver transplantation, there are no licensed therapies that target the full complement of disease features. The presence of some shared pathogenic mechanisms and histological features in NAFLD and ALD suggests that it may be possible to develop markers for prognostication or staging, or indeed new therapeutic tools to treat both conditions. One such example of an approach exists in the form of the NACHT-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway. Activation of the NLRP3 inflammasome results in hepatocyte pyroptosis, persistence, and amplification of liver inflammation and activation of profibrogenic signaling cascades. Thus, targeting elements of the pathway in NAFLD and ALD may provide a tractable route to pharmacological therapy. In this review, we summarize the contribution of this inflammasome to disease and review the current options for therapy.
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Carnagarin R, Tan K, Adams L, Matthews VB, Kiuchi MG, Marisol Lugo Gavidia L, Lambert GW, Lambert EA, Herat LY, Schlaich MP. Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)-A Condition Associated with Heightened Sympathetic Activation. Int J Mol Sci 2021; 22:ijms22084241. [PMID: 33921881 PMCID: PMC8073135 DOI: 10.3390/ijms22084241] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease affecting a quarter of the global population and is often associated with adverse health outcomes. The increasing prevalence of MAFLD occurs in parallel to that of metabolic syndrome (MetS), which in fact plays a major role in driving the perturbations of cardiometabolic homeostasis. However, the mechanisms underpinning the pathogenesis of MAFLD are incompletely understood. Compelling evidence from animal and human studies suggest that heightened activation of the sympathetic nervous system is a key contributor to the development of MAFLD. Indeed, common treatment strategies for metabolic diseases such as diet and exercise to induce weight loss have been shown to exert their beneficial effects at least in part through the associated sympathetic inhibition. Furthermore, pharmacological and device-based approaches to reduce sympathetic activation have been demonstrated to improve the metabolic alterations frequently present in patients with obesity, MetSand diabetes. Currently available evidence, while still limited, suggests that sympathetic activation is of specific relevance in the pathogenesis of MAFLD and consequentially may offer an attractive therapeutic target to attenuate the adverse outcomes associated with MAFLD.
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Affiliation(s)
- Revathy Carnagarin
- Dobney Hypertension Centre, School of Medicine—Royal Perth Hospital Unit, RPH Research Foundation, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6000, Australia; (R.C.); (K.T.); (V.B.M.); (M.G.K.); (L.M.L.G.); (L.Y.H.)
| | - Kearney Tan
- Dobney Hypertension Centre, School of Medicine—Royal Perth Hospital Unit, RPH Research Foundation, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6000, Australia; (R.C.); (K.T.); (V.B.M.); (M.G.K.); (L.M.L.G.); (L.Y.H.)
| | - Leon Adams
- Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6009, Australia;
| | - Vance B. Matthews
- Dobney Hypertension Centre, School of Medicine—Royal Perth Hospital Unit, RPH Research Foundation, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6000, Australia; (R.C.); (K.T.); (V.B.M.); (M.G.K.); (L.M.L.G.); (L.Y.H.)
| | - Marcio G. Kiuchi
- Dobney Hypertension Centre, School of Medicine—Royal Perth Hospital Unit, RPH Research Foundation, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6000, Australia; (R.C.); (K.T.); (V.B.M.); (M.G.K.); (L.M.L.G.); (L.Y.H.)
| | - Leslie Marisol Lugo Gavidia
- Dobney Hypertension Centre, School of Medicine—Royal Perth Hospital Unit, RPH Research Foundation, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6000, Australia; (R.C.); (K.T.); (V.B.M.); (M.G.K.); (L.M.L.G.); (L.Y.H.)
| | - Gavin W. Lambert
- Iverson Health Innovation Research Institute and School of Health Sciences, Swinburne University of Technology, Melbourne, VIC 3122, Australia; (G.W.L.); (E.A.L.)
- Human Neurotransmitter Lab, Melbourne, VIC 3004, Australia
| | - Elisabeth A. Lambert
- Iverson Health Innovation Research Institute and School of Health Sciences, Swinburne University of Technology, Melbourne, VIC 3122, Australia; (G.W.L.); (E.A.L.)
- Human Neurotransmitter Lab, Melbourne, VIC 3004, Australia
| | - Lakshini Y. Herat
- Dobney Hypertension Centre, School of Medicine—Royal Perth Hospital Unit, RPH Research Foundation, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6000, Australia; (R.C.); (K.T.); (V.B.M.); (M.G.K.); (L.M.L.G.); (L.Y.H.)
| | - Markus P. Schlaich
- Dobney Hypertension Centre, School of Medicine—Royal Perth Hospital Unit, RPH Research Foundation, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA 6000, Australia; (R.C.); (K.T.); (V.B.M.); (M.G.K.); (L.M.L.G.); (L.Y.H.)
- Neurovascular Hypertension and Kidney Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
- Departments of Cardiology and Nephrology, Royal Perth Hospital, Perth, WA 6000, Australia
- Correspondence: ; Tel.: +61-8-9224-0382; Fax: +61-8-9224-0374
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Tomé-Carneiro J, Crespo MC, López de Las Hazas MC, Visioli F, Dávalos A. Olive oil consumption and its repercussions on lipid metabolism. Nutr Rev 2021; 78:952-968. [PMID: 32299100 DOI: 10.1093/nutrit/nuaa014] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Consumption of highly processed foods, such as those high in trans fats and free sugars, coupled with sedentarism and chronic stress increases the risk of obesity and cardiometabolic disorders, while adherence to a Mediterranean diet is inversely associated with the prevalence of such diseases. Olive oil is the main source of fat in the Mediterranean diet. Data accumulated thus far show consumption of extra virgin, (poly)phenol-rich olive oil to be associated with specific health benefits. Of note, recommendations for consumption based on health claims refer to the phenolic content of extra virgin olive oil as beneficial. However, even though foods rich in monounsaturated fatty acids, such as olive oil, are healthier than foods rich in saturated and trans fats, their inordinate use can lead to adverse effects on health. The aim of this review was to summarize the data on olive oil consumption worldwide and to critically examine the literature on the potential adverse effects of olive oil and its main components, particularly any effects on lipid metabolism. As demonstrated by substantial evidence, extra virgin olive oil is healthful and should be preferentially used within the context of a balanced diet, but excessive consumption may lead to adverse consequences.
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Affiliation(s)
- João Tomé-Carneiro
- Laboratory of Functional Foods, Madrid Institute for Advanced Studies (IMDEA)-Food, Campus of International Excellence UAM + CSIC, Madrid, Spain
| | - María Carmen Crespo
- Laboratory of Functional Foods, Madrid Institute for Advanced Studies (IMDEA)-Food, Campus of International Excellence UAM + CSIC, Madrid, Spain
| | - María Carmen López de Las Hazas
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, Campus of International Excellence UAM + CSIC, Madrid, Spain
| | - Francesco Visioli
- Laboratory of Functional Foods, Madrid Institute for Advanced Studies (IMDEA)-Food, Campus of International Excellence UAM + CSIC, Madrid, Spain.,Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Alberto Dávalos
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, Campus of International Excellence UAM + CSIC, Madrid, Spain
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Scapaticci S, D’Adamo E, Mohn A, Chiarelli F, Giannini C. Non-Alcoholic Fatty Liver Disease in Obese Youth With Insulin Resistance and Type 2 Diabetes. Front Endocrinol (Lausanne) 2021; 12:639548. [PMID: 33889132 PMCID: PMC8056131 DOI: 10.3389/fendo.2021.639548] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
Currently, Non-Alcoholic Fatty Liver Disease (NAFLD) is the most prevalent form of chronic liver disease in children and adolescents worldwide. Simultaneously to the epidemic spreading of childhood obesity, the rate of affected young has dramatically increased in the last decades with an estimated prevalence of NAFLD of 3%-10% in pediatric subjects in the world. The continuous improvement in NAFLD knowledge has significantly defined several risk factors associated to the natural history of this complex liver alteration. Among them, Insulin Resistance (IR) is certainly one of the main features. As well, not surprisingly, abnormal glucose tolerance (prediabetes and diabetes) is highly prevalent among children/adolescents with biopsy-proven NAFLD. In addition, other factors such as genetic, ethnicity, gender, age, puberty and lifestyle might affect the development and progression of hepatic alterations. However, available data are still lacking to confirm whether IR is a risk factor or a consequence of hepatic steatosis. There is also evidence that NAFLD is the hepatic manifestation of Metabolic Syndrome (MetS). In fact, NAFLD often coexist with central obesity, impaired glucose tolerance, dyslipidemia, and hypertension, which represent the main features of MetS. In this Review, main aspects of the natural history and risk factors of the disease are summarized in children and adolescents. In addition, the most relevant scientific evidence about the association between NAFLD and metabolic dysregulation, focusing on clinical, pathogenetic, and histological implication will be provided with some focuses on the main treatment options.
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Affiliation(s)
| | | | | | | | - Cosimo Giannini
- Department of Pediatrics, University of Chieti, Chieti, Italy
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Fawzy MH, Saeed NM, El-Sherbiny DA, El-Demerdash E. Eugenol modulates insulin sensitivity by upregulating insulin receptor substrate-2 in non-alcoholic fatty liver disease in rats. J Pharm Pharmacol 2021; 73:846-854. [PMID: 33822104 DOI: 10.1093/jpp/rgab032] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 02/13/2021] [Indexed: 12/27/2022]
Abstract
OBJECTIVES The purpose of this study was to estimate the possible modulatory effect of Eugenol (EUG) on insulin resistance (IR) and liver fibrosis in high-fat diet (HFD)-induced experimental non-alcoholic fatty liver disease (NAFLD) in rats. It has been shown that EUG, a natural phenolic compound, has anti-hyperglycaemic, antioxidant and anti-inflammatory actions. METHODS For 8 consecutive weeks, standard rat chow diet (control group, EUG only treated group) or HFD (HFD group and HFD+EUG-treated group) were fed to rats daily. HFD+EUG-treated group and EUG only treated group were administered EUG (10 mg/kg) orally three times per week. Various indices of hepatotoxicity, oxidative stress, indicators of inflammation and liver fibrosis were investigated. KEY FINDINGS HFD-induced liver transaminases and triglycerides (TGs) were significantly decreased and histopathological lesions were improved with EUG treatment. EUG significantly improved IR evoked by HFD, as demonstrated by Homeostasis model assessment for insulin resistance (HOMA-IR) and increased insulin receptor substrate-2 (IRS-2) sensitivity. In addition, EUG improved oxidative stress damage elicited by HFD as shown by the restoration of reduced glutathione (GSH) level and nuclear factor erythroid-2-related factor 2 (Nrf-2) expression and plummeting lipid peroxidation. Further, EUG lessened pro-inflammatory cytokines surge [tumour necrosis factor-α (TNF-α) and IL-6] via inhibiting nuclear factor-κB (NF-κB) stimulation. As markers of fibrosis, EUG reduced collagen accumulation and smooth muscle alpha actin (SMaA) and TGF-β expression. CONCLUSIONS EUG may have protective effect against progression of fibrosis in NAFLD. The antifibrotic effect of EUG is probably due to EUG's antioxidant, anti-inflammatory and anti-hyperglycaemic.
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Affiliation(s)
- Mariam H Fawzy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Noha M Saeed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Doaa A El-Sherbiny
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Ebtehal El-Demerdash
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
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Valladolid-Acebes I, Åvall K, Recio-López P, Moruzzi N, Bryzgalova G, Björnholm M, Krook A, Alonso EF, Ericsson M, Landfors F, Nilsson SK, Berggren PO, Juntti-Berggren L. Lowering apolipoprotein CIII protects against high-fat diet-induced metabolic derangements. SCIENCE ADVANCES 2021; 7:7/11/eabc2931. [PMID: 33712458 PMCID: PMC7954448 DOI: 10.1126/sciadv.abc2931] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 01/27/2021] [Indexed: 02/05/2023]
Abstract
Increased levels of apolipoprotein CIII (apoCIII), a key regulator of lipid metabolism, result in obesity-related metabolic derangements. We investigated mechanistically whether lowering or preventing high-fat diet (HFD)–induced increase in apoCIII protects against the detrimental metabolic consequences. Mice, first fed HFD for 10 weeks and thereafter also given an antisense (ASO) to lower apoCIII, already showed reduced levels of apoCIII and metabolic improvements after 4 weeks, despite maintained obesity. Prolonged ASO treatment reversed the metabolic phenotype due to increased lipase activity and receptor-mediated hepatic uptake of lipids. Fatty acids were transferred to the ketogenic pathway, and ketones were used in brown adipose tissue (BAT). This resulted in no fat accumulation and preserved morphology and function of liver and BAT. If ASO treatment started simultaneously with the HFD, mice remained lean and metabolically healthy. Thus, lowering apoCIII protects against and reverses the HFD-induced metabolic phenotype by promoting physiological insulin sensitivity.
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Affiliation(s)
- Ismael Valladolid-Acebes
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden
| | - Karin Åvall
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden
| | - Patricia Recio-López
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden
| | - Noah Moruzzi
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden
| | - Galyna Bryzgalova
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden
| | - Marie Björnholm
- Department of Molecular Medicine and Surgery, Integrative Physiology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Anna Krook
- Department of Physiology and Pharmacology, C3, Integrative Physiology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Elena Fauste Alonso
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden.,Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Montepríncipe, Boadilla del Monte, Madrid, Spain
| | - Madelene Ericsson
- Department of Medical Biosciences, Unit of Physiological Chemistry 6M, Umeå University, SE-901 85 Umeå, Sweden
| | - Fredrik Landfors
- Department of Medical Biosciences, Unit of Physiological Chemistry 6M, Umeå University, SE-901 85 Umeå, Sweden
| | - Stefan K Nilsson
- Department of Medical Biosciences, Unit of Physiological Chemistry 6M, Umeå University, SE-901 85 Umeå, Sweden
| | - Per-Olof Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden.,Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Republic of Korea.,Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.,Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637553, Singapore.,Center for Diabetes and Metabolism Research, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, PR China
| | - Lisa Juntti-Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden.
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Fructo-Oligosaccharides and Pectins Enhance Beneficial Effects of Raspberry Polyphenols in Rats with Nonalcoholic Fatty Liver. Nutrients 2021; 13:nu13030833. [PMID: 33802455 PMCID: PMC8001257 DOI: 10.3390/nu13030833] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 12/12/2022] Open
Abstract
In recent years, nonalcoholic fatty liver disorders have become one of the most common liver pathologies; therefore, it is necessary to investigate the dietary compounds that may support the regulation of liver metabolism and related inflammatory processes. The present study examines the effect of raspberry polyphenolic extract (RE) combined with fructo-oligosaccharides (FOSs) or pectins (PECs) on caecal microbial fermentation, liver lipid metabolism and inflammation in rats with fatty liver induced by an obesogenic diet. The combination of RE with FOSs or PECs reduced the production of short-chain fatty acids in the caecum. RE combined with FOSs exerted the most favourable effects on liver lipid metabolism by decreasing liver fat, cholesterol, triglyceride content and hepatic steatosis. RE and FOSs reduced lobular and portal inflammatory cell infiltration and IL-6 plasma levels. These effects might be related to a decrease in the hepatic expressions of PPARγ and ANGPTL4. In conclusion, PECs and FOSs enhanced the effects of RE against disorders related to nonalcoholic fatty liver; however, the most effective dietary treatment in the regulation of liver lipid metabolism and inflammation caused by an obesogenic diet was the combination of RE with FOSs.
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Yao M, Teng H, Lv Q, Gao H, Guo T, Lin Y, Gao S, Ma M, Chen L. Anti-hyperglycemic effects of dihydromyricetin in streptozotocin-induced diabetic rats. FOOD SCIENCE AND HUMAN WELLNESS 2021. [DOI: 10.1016/j.fshw.2021.02.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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