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Jiang Y, Wu L, Zhu X, Bian H, Gao X, Xia M. Advances in management of metabolic dysfunction-associated steatotic liver disease: from mechanisms to therapeutics. Lipids Health Dis 2024; 23:95. [PMID: 38566209 PMCID: PMC10985930 DOI: 10.1186/s12944-024-02092-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 03/26/2024] [Indexed: 04/04/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease that affects over 30% of the world's population. For decades, the heterogeneity of non-alcoholic fatty liver disease (NAFLD) has impeded our understanding of the disease mechanism and the development of effective medications. However, a recent change in the nomenclature from NAFLD to MASLD emphasizes the critical role of systemic metabolic dysfunction in the pathophysiology of this disease and therefore promotes the progress in the pharmaceutical treatment of MASLD. In this review, we focus on the mechanism underlying the abnormality of hepatic lipid metabolism in patients with MASLD, and summarize the latest progress in the therapeutic medications of MASLD that target metabolic disorders.
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Affiliation(s)
- Yuxiao Jiang
- Department of Endocrinology and Metabolism, Zhongshan Hospital and Fudan Institute for Metabolic Diseases, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China
| | - Lili Wu
- Department of Endocrinology and Metabolism, Zhongshan Hospital and Fudan Institute for Metabolic Diseases, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China
- Department of Integrated Medicine, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xiaopeng Zhu
- Department of Endocrinology and Metabolism, Zhongshan Hospital and Fudan Institute for Metabolic Diseases, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China
| | - Hua Bian
- Department of Endocrinology and Metabolism, Zhongshan Hospital and Fudan Institute for Metabolic Diseases, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital and Fudan Institute for Metabolic Diseases, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China.
| | - Mingfeng Xia
- Department of Endocrinology and Metabolism, Zhongshan Hospital and Fudan Institute for Metabolic Diseases, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China.
- Department of Endocrinology and Metabolism, Wusong Branch of Zhongshan Hospital, Fudan University, Shanghai, China.
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2
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Zhu M, Dagah OMA, Silaa BB, Lu J. Thioredoxin/Glutaredoxin Systems and Gut Microbiota in NAFLD: Interplay, Mechanism, and Therapeutical Potential. Antioxidants (Basel) 2023; 12:1680. [PMID: 37759983 PMCID: PMC10525532 DOI: 10.3390/antiox12091680] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 08/20/2023] [Accepted: 08/25/2023] [Indexed: 09/29/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common clinical disease, and its pathogenesis is closely linked to oxidative stress and gut microbiota dysbiosis. Recently accumulating evidence indicates that the thioredoxin and glutaredoxin systems, the two thiol-redox dependent antioxidant systems, are the key players in the NAFLD's development and progression. However, the effects of gut microbiota dysbiosis on the liver thiol-redox systems are not well clarified. This review explores the role and mechanisms of oxidative stress induced by bacteria in NAFLD while emphasizing the crucial interplay between gut microbiota dysbiosis and Trx mediated-redox regulation. The paper explores how dysbiosis affects the production of specific gut microbiota metabolites, such as trimethylamine N-oxide (TMAO), lipopolysaccharides (LPS), short-chain fatty acids (SCFAs), amino acids, bile acid, and alcohol. These metabolites, in turn, significantly impact liver inflammation, lipid metabolism, insulin resistance, and cellular damage through thiol-dependent redox signaling. It suggests that comprehensive approaches targeting both gut microbiota dysbiosis and the thiol-redox antioxidant system are essential for effectively preventing and treating NAFLD. Overall, comprehending the intricate relationship between gut microbiota dysbiosis and thiol-redox systems in NAFLD holds significant promise in enhancing patient outcomes and fostering the development of innovative therapeutic interventions.
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Affiliation(s)
| | | | | | - Jun Lu
- Engineering Research Center of Coptis Development and Utilization/Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education (Southwest University), College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China; (M.Z.); (O.M.A.D.); (B.B.S.)
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Halle JL, Counts BR, Paez HG, Baumfalk DR, Zhang Q, Mohamed JS, Glazer ES, Puppa MJ, Smuder AJ, Alway SE, Carson JA. Recovery from FOLFOX chemotherapy-induced systemic and skeletal muscle metabolic dysfunction in mice. Am J Physiol Endocrinol Metab 2023; 325:E132-E151. [PMID: 37378624 PMCID: PMC10393342 DOI: 10.1152/ajpendo.00096.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/22/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023]
Abstract
FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) chemotherapy is used to treat colorectal cancer and can acutely induce metabolic dysfunction. However, the lasting effects on systemic and skeletal muscle metabolism after treatment cessation are poorly understood. Therefore, we investigated the acute and lasting effects of FOLFOX chemotherapy on systemic and skeletal muscle metabolism in mice. Direct effects of FOLFOX in cultured myotubes were also investigated. Male C57BL/6J mice completed four cycles (acute) of FOLFOX or PBS. Subsets were allowed to recover for 4 wk or 10 wk. Comprehensive Laboratory Animal Monitoring System (CLAMS) metabolic measurements were performed for 5 days before study endpoint. C2C12 myotubes were treated with FOLFOX for 24 hr. Acute FOLFOX attenuated body mass and body fat accretion independent of food intake or cage activity. Acute FOLFOX decreased blood glucose, oxygen consumption (V̇o2), carbon dioxide production (V̇co2), energy expenditure, and carbohydrate (CHO) oxidation. Deficits in V̇o2 and energy expenditure remained at 10 wk. CHO oxidation remained disrupted at 4 wk but returned to control levels after 10 wk. Acute FOLFOX reduced muscle COXIV enzyme activity, AMPK(T172), ULK1(S555), and LC3BII protein expression. Muscle LC3BII/I ratio was associated with altered CHO oxidation (r = 0.75, P = 0.03). In vitro, FOLFOX suppressed myotube AMPK(T172), ULK1(S555), and autophagy flux. Recovery for 4 wk normalized skeletal muscle AMPK and ULK1 phosphorylation. Our results provide evidence that FOLFOX disrupts systemic metabolism, which is not readily recoverable after treatment cessation. FOLFOX effects on skeletal muscle metabolic signaling did recover. Further investigations are warranted to prevent and treat FOLFOX-induced metabolic toxicities that negatively impact survival and life quality of patients with cancer.NEW & NOTEWORTHY The present study demonstrates that FOLFOX chemotherapy induces long-lasting deficits in systemic metabolism. Interestingly, FOLFOX modestly suppressed skeletal muscle AMPK and autophagy signaling in vivo and in vitro. The FOLFOX-induced suppression of muscle metabolic signaling recovered after treatment cessation, independent of systemic metabolic dysfunction. Future research should investigate if activating AMPK during treatment can prevent long-term toxicities to improve health and quality of life of patients with cancer and survivors.
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Affiliation(s)
- Jessica L Halle
- Integrative Muscle Biology Laboratory, Division of Regenerative and Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Brittany R Counts
- Integrative Muscle Biology Laboratory, Division of Regenerative and Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Hector G Paez
- Laboratory of Muscle Biology and Sarcopenia, Department of Physical Therapy, College of Health Professions, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Dryden R Baumfalk
- Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, Florida, United States
| | - Quan Zhang
- Integrative Muscle Biology Laboratory, Division of Regenerative and Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Junaith S Mohamed
- Laboratory of Muscle and Nerve, Department of Diagnostic and Health Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Evan S Glazer
- Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Melissa J Puppa
- College of Health Sciences, The University of Memphis, Memphis, Tennessee, United States
| | - Ashley J Smuder
- Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, Florida, United States
| | - Stephen E Alway
- Laboratory of Muscle Biology and Sarcopenia, Department of Physical Therapy, College of Health Professions, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - James A Carson
- Integrative Muscle Biology Laboratory, Division of Regenerative and Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, Tennessee, United States
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Wang D, Ji DC, Yu CY, Wu DN, Qi L. Research progress on the mitochondrial mechanism of age-related non-alcoholic fatty liver. World J Gastroenterol 2023; 29:1982-1993. [PMID: 37155524 PMCID: PMC10122792 DOI: 10.3748/wjg.v29.i13.1982] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/20/2023] [Accepted: 03/13/2023] [Indexed: 04/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. Reduced activity and slower metabolism in the elderly affect the balance of lipid metabolism in the liver leading to the accumulation of lipids. This affects the mitochondrial respiratory chain and the efficiency of β-oxidation and induces the overproduction of reactive oxygen species. In addition, the dynamic balance of the mitochondria is disrupted during the ageing process, which inhibits its phagocytic function and further aggravates liver injury, leading to a higher incidence of NAFLD in the elderly population. The present study reviewed the manifestations, role and mechanism of mitochondrial dysfunction in the progression of NAFLD in the elderly. Based on the understanding of mitochondrial dysfunction and abnormal lipid metabolism, this study discusses the treatment strategies and the potential therapeutic targets for NAFLD, including lipid accumulation, antioxidation, mitophagy and liver-protecting drugs. The purpose is to provide new ideas for the development of innovative drugs for the prevention and treatment of NAFLD.
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Affiliation(s)
- Dan Wang
- College of Basic Medicine, Beihua University, Jilin 132013, Jilin Province, China
| | - Duo-Chun Ji
- College of Basic Medicine, Beihua University, Jilin 132013, Jilin Province, China
| | - Chun-Yan Yu
- College of Basic Medicine, Beihua University, Jilin 132013, Jilin Province, China
| | - Dan-Ni Wu
- College of Basic Medicine, Beihua University, Jilin 132013, Jilin Province, China
| | - Ling Qi
- Central Laboratory, Qingyuan People's Hospital, Qingyuan 511518, Guangdong Province, China
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Yao M, Zhou P, Qin YY, Wang L, Yao DF. Mitochondrial carnitine palmitoyltransferase-II dysfunction: A possible novel mechanism for nonalcoholic fatty liver disease in hepatocarcinogenesis. World J Gastroenterol 2023; 29:1765-1778. [PMID: 37032731 PMCID: PMC10080702 DOI: 10.3748/wjg.v29.i12.1765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/04/2022] [Accepted: 03/13/2023] [Indexed: 03/28/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease has been characterized by the lipid accumulation with injury of hepatocytes and has become one of the most common chronic liver diseases in the world. The complex mechanisms of NAFLD formation are still under identification. Carnitine palmitoyltransferase-II (CPT-II) on inner mitochondrial membrane (IMM) regulates long chain fatty acid β-oxidation, and its abnormality has had more and more attention paid to it by basic and clinical research in NAFLD. The sequences of its peptide chain and DNA nucleotides have been identified, and the catalytic activity of CPT-II is affected on its gene mutations, deficiency, enzymatic thermal instability, circulating carnitine level and so on. Recently, the CPT-II dysfunction has been discovered in models of liver lipid accumulation. Meanwhile, the malignant transformation of hepatocyte-related CD44+ stem T cell activation, high levels of tumor-related biomarkers (AFP, GPC3) and abnormal activation of Wnt3a expression as a key signal molecule of the Wnt/β-catenin pathway run parallel to the alterations of hepatocyte pathology. This review focuses on some of the progress of CPT-II inactivity on IMM with liver fatty accumulation as a possible novel pathogenesis for NAFLD in hepatocarcinogenesis.
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Affiliation(s)
- Min Yao
- Department of Medical Immunology, Medical School of Nantong University & Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Ping Zhou
- Department of Medical Immunology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Yan-Yan Qin
- Department of Medical Immunology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Li Wang
- Research Center for Intelligent Information Technology, Nantong University, Nantong 226019, Jiangsu Province, China
| | - Deng-Fu Yao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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Tu T, Alba MM, Datta AA, Hong H, Hua B, Jia Y, Khan J, Nguyen P, Niu X, Pammidimukkala P, Slarve I, Tang Q, Xu C, Zhou Y, Stiles BL. Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis. Front Oncol 2022; 12:958696. [PMID: 36276076 PMCID: PMC9581256 DOI: 10.3389/fonc.2022.958696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/17/2022] [Indexed: 12/02/2022] Open
Abstract
Obesity confers an independent risk for carcinogenesis. Classically viewed as a genetic disease, owing to the discovery of tumor suppressors and oncogenes, genetic events alone are not sufficient to explain the progression and development of cancers. Tumor development is often associated with metabolic and immunological changes. In particular, obesity is found to significantly increase the mortality rate of liver cancer. As its role is not defined, a fundamental question is whether and how metabolic changes drive the development of cancer. In this review, we will dissect the current literature demonstrating that liver lipid dysfunction is a critical component driving the progression of cancer. We will discuss the involvement of inflammation in lipid dysfunction driven liver cancer development with a focus on the involvement of liver macrophages. We will first discuss the association of steatosis with liver cancer. This will be followed with a literature summary demonstrating the importance of inflammation and particularly macrophages in the progression of liver steatosis and highlighting the evidence that macrophages and macrophage produced inflammatory mediators are critical for liver cancer development. We will then discuss the specific inflammatory mediators and their roles in steatosis driven liver cancer development. Finally, we will summarize the molecular pattern (PAMP and DAMP) as well as lipid particle signals that are involved in the activation, infiltration and reprogramming of liver macrophages. We will also discuss some of the therapies that may interfere with lipid metabolism and also affect liver cancer development.
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Affiliation(s)
- Taojian Tu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Mario M. Alba
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Aditi A. Datta
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Handan Hong
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Brittney Hua
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Yunyi Jia
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Jared Khan
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Phillip Nguyen
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Xiatoeng Niu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Pranav Pammidimukkala
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Ielyzaveta Slarve
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Qi Tang
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Chenxi Xu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Yiren Zhou
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Bangyan L. Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- *Correspondence: Bangyan L. Stiles,
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Hughey CC, Puchalska P, Crawford PA. Integrating the contributions of mitochondrial oxidative metabolism to lipotoxicity and inflammation in NAFLD pathogenesis. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159209. [DOI: 10.1016/j.bbalip.2022.159209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 06/25/2022] [Accepted: 07/27/2022] [Indexed: 11/28/2022]
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Vidé J, Bonafos B, Fouret G, Benlebna M, Poupon J, Jover B, Casas F, Jouy N, Feillet-Coudray C, Gaillet S, Coudray C. Spirulina platensis and silicon-enriched spirulina equally improve glucose tolerance and decrease the enzymatic activity of hepatic NADPH oxidase in obesogenic diet-fed rats. Food Funct 2019; 9:6165-6178. [PMID: 30431036 DOI: 10.1039/c8fo02037j] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The prevalence of metabolic syndrome components, such as obesity, glucose intolerance and hepatic steatosis, is rapidly increasing and becoming a major issue of public health. The present work was designed to determine the effects of Spirulina platensis (Sp) algae and silicon-enriched Sp on major metabolic syndrome components in obesogenic diet-fed rats. Forty male Wistar rats were divided into 4 groups. Ten rats were fed a control diet and 30 rats were fed a high fat (HF) diet. The HF groups were divided into three groups and supplemented with placebo or Sp or Si-enriched Sp for 12 weeks. Dietary intake and body weight were recorded. Oral glucose tolerance test and surrogate metabolic syndrome (insulin, leptin, adiponectin and lipids), mitochondrial function (enzymatic activity of respiratory chain complexes and β-hydroxyacyl-CoA dehydrogenase), NADPH oxidase activity and several long-established oxidative stress markers were measured in the blood and liver. The HF diet induced obesity, glucose intolerance, hepatic steatosis and huge metabolic alterations, associated with higher NADPH oxidase activity and lower hepatic sulfhydryl group and glutathione contents. Otherwise, the Sp and Sp + Si supplements showed some interesting effects on rat characteristics and particularly on blood and hepatic metabolic parameters. Indeed, the intake of Sp or Sp + Si mainly improved glucose tolerance and decreased the enzymatic activity of hepatic NADPH oxidase. Overall, Si supplementation of spirulina does not appear to have more beneficial effects than spirulina alone. Other experiments with different species of rats/mice, different diets or different durations of diet intake should be undertaken to confirm or invalidate these results.
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Affiliation(s)
- Joris Vidé
- DMEM, INRA, Univ. Montpellier, Montpellier, France.
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20-Week follow-up of hepatic steatosis installation and liver mitochondrial structure and activity and their interrelation in rats fed a high-fat-high-fructose diet. Br J Nutr 2019; 119:368-380. [PMID: 29498345 DOI: 10.1017/s0007114517003713] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The incidence of obesity and its metabolic complications are rapidly increasing and become a major public health issue. This trend is associated with an increase in the prevalence of non-alcoholic fatty liver disease (NAFLD), insulin resistance and diabetes. The sequence of events leading to NAFLD progression and mitochondrial dysfunction and their interrelation remains to be elucidated. This study aimed to explore the installation and progression of NAFLD and its association with the liver mitochondrial structure and activity changes in rats fed an obesogenic diet up to 20 weeks. Male Wistar rats were fed either a standard or high-fat-high-fructose (HFHFR) diet and killed on 4, 8, 12, 16 and 20 weeks of diet intake. Rats fed the HFHFR diet developed mildly overweight, associated with increased adipose tissue weight, hepatic steatosis, hyperglycaemia and hyperinsulinaemia after 8 weeks of HFHFR diet. Hepatic steatosis and many biochemical modifications plateaued at 8-12 weeks of HFHFR diet with slight amelioration afterwards. Interestingly, several biochemical and physiological parameters of mitochondrial function, as well as its phospholipid composition, in particular cardiolipin content, were tightly related to hepatic steatosis installation. These results showed once again the interrelation between hepatic steatosis development and mitochondrial activity alterations without being able to say whether the mitochondrial alterations preceded or followed the installation/progression of hepatic steatosis. Because both hepatic steatosis and mitochondrial alterations occurred as early as 4 weeks of diet, future studies should consider these four 1st weeks to reveal the exact interconnection between these major consequences of obesogenic diet intake.
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Tang R, Yang Q, Lin S, Feng Y, Yang J, Lv Q, Wu G, Hu J. Preventive or Curative Administration of Taurine Regulates Lipid Metabolism in the Liver of Rats with Alcoholic Liver Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1155:119-131. [PMID: 31468391 DOI: 10.1007/978-981-13-8023-5_11] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Excessive consumption causes alcoholic liver disease (ALD), which injures hepatocytes and induces imbalance of lipid metabolism. Taurine is known to protect the liver from various liver injuries, and relieve lipid profile. Our previous studies also found that taurine can prevent or cure ALD, reduce fat deposition, but the mechanism remains unclear. In the present study, ALD rat model was established by administration of alcohol, pyrazole and high fat diet. Two percent taurine was administered at the same time or after ALD model establishment. Serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), serum and hepatic TC, TG, HDL-C and LDL-C were analyzed. Real-Time RT-PCR was conducted to detect the mRNA expressions of fatty acid synthetase (FAS), acetyl-CoA catboxylase (ACC), carnitine palmitoyl transferase 1 (CPT-1), 3-Hydroxy-3-methyl glutaric acid acyl Coenzyme A reductase (HMGCR), peroxisome proliferators activated receptor α (PPARα) and sterol regulatory element-binding protein 1c (SREBP-1c). The results showed that serum ALT, AST, serum and hepatic TC, TG and LDL-C were higher, while HDL-C in ALD model rats was lower than normal rats, the changes of which can be significantly relieved by taurine administration. mRNA expressions of ACC, FAS, CPT-1, HMGCR, PPARα and SREBP-1c which were significantly changed by ethanol can also be regulated by taurine. The results indicated that taurine can prevent and repair hepatic injury of ALD rats and balance lipid metabolism indexes in the liver, the mechanisms may involves in the regulation of related enzymes and transcriptional regulators participated in lipid metabolism.
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Affiliation(s)
- Riyi Tang
- Liaoning Provincial Key Laboratory of Zoonosis, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, Liaoning, People's Republic of China
| | - Qunhui Yang
- Liaoning Provincial Key Laboratory of Zoonosis, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, Liaoning, People's Republic of China
| | - Shumei Lin
- Liaoning Provincial Key Laboratory of Zoonosis, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, Liaoning, People's Republic of China
| | - Ying Feng
- Liaoning Provincial Key Laboratory of Zoonosis, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, Liaoning, People's Republic of China
| | - Jiancheng Yang
- Liaoning Provincial Key Laboratory of Zoonosis, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, Liaoning, People's Republic of China
| | - Qiufeng Lv
- Liaoning Provincial Key Laboratory of Zoonosis, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, Liaoning, People's Republic of China
| | - Gaofeng Wu
- Liaoning Provincial Key Laboratory of Zoonosis, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, Liaoning, People's Republic of China
| | - Jianmin Hu
- Liaoning Provincial Key Laboratory of Zoonosis, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, Liaoning, People's Republic of China
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Zhang Y, Wang M, Dong H, Yu X, Zhang J. Anti-hypoglycemic and hepatocyte-protective effects of hyperoside from Zanthoxylum bungeanum leaves in mice with high-carbohydrate/high-fat diet and alloxan-induced diabetes. Int J Mol Med 2017; 41:77-86. [PMID: 29115390 PMCID: PMC5746319 DOI: 10.3892/ijmm.2017.3211] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 10/17/2017] [Indexed: 12/12/2022] Open
Abstract
The development of diabetes mellitus (DM) is accompanied by hyperglycemia-induced oxidative stress. Hyperoside is a major bioactive component in Zanthoxylum bungeanum leaves (HZL) and is a natural antioxidant. However, the effects of HZL on DM and its mechanisms of action remain undefined. The present study evaluated the anti-hypoglycemic and hepatocyte-protective effects of HZL in mice with diabetes induced by a high-carbohydrate/high-fat diet (HFD) and alloxan. We also aimed to eludicate the underlying mechanisms. Our resutls demonstrated that the administration of HZL significantly reduced body weight gain, serum glucose levels and insulin levels in diabetic mice compared with the vehicle-treated mice. In addition, the levels of dyslipidemia markers including total cholesterol, triglyceride and low-density lipoprotein cholesterol in the HFD-treated mice were markedly decreased. Further experiments using hepatocytes from mice revealed that HZL significantly attenuated liver injury associated with DM compared with vehicle treatment, as evidenced by lower levels of alanine aminotransferase and aspartate aminotransferase in serum and by lower levels of lipid peroxidation, nitric oxide content and inducible nitric oxide synthase activity in liver tissues. Nuclear factor-κB (NF-κB) and mitogen-associated protein kinase (MAPK) signaling pathways were investigated to elucidate the molecular mechanisms responsible for the protective effects of HZL against diabetic liver injury. The results indicated that HZL inhibited the phosphorylation of p65/NF-κB, MAPK (including p38, JNK and ERK1/2) and activating transcription factor 3 protein expression, with an additional suppression of Bax, cytochrome c, caspase-9 and caspase-3 in the liver tissues of diabetic mice. Taken together, our findings suggest that HZL, which was effective in inhibiting oxidative stress-related pathways may be beneficial for use in the treatment of DM.
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Affiliation(s)
- Yali Zhang
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, P.R. China
| | - Mimi Wang
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, P.R. China
| | - Huanhuan Dong
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, P.R. China
| | - Xiaomin Yu
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, P.R. China
| | - Jingfang Zhang
- College of Forestry, Northwest A&F University, Xianyang, Shaanxi 712100, P.R. China
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circRNA_0046367 Prevents Hepatoxicity of Lipid Peroxidation: An Inhibitory Role against Hepatic Steatosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:3960197. [PMID: 29018509 PMCID: PMC5605923 DOI: 10.1155/2017/3960197] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 06/26/2017] [Accepted: 07/06/2017] [Indexed: 12/20/2022]
Abstract
Hepatic steatosis reflects the miRNA-related pathological disorder with triglyceride accumulation and lipid peroxidation, which leads to nonalcoholic steatohepatitis, liver fibrosis/cirrhosis, and even hepatocellular carcinoma. Circular RNA (circRNA)/miRNA interaction reveals a novel layer of epigenetic regulation, yet the miRNA-targeting circRNA remains uncertain in hepatic steatosis. Here, we uncover circRNA_0046367 to be endogenous modulator of miR-34a that underlies hepatic steatosis. In contrast to its expression loss during the hepatocellular steatosis in vivo and in vitro, circRNA_0046367 normalization abolished miR-34a's inhibitory effect on peroxisome proliferator-activated receptor α (PPARα) via blocking the miRNA/mRNA interaction with miRNA response elements (MREs). PPARα restoration led to the transcriptional activation of genes associated with lipid metabolism, including carnitine palmitoyltransferase 2 (CPT2) and acyl-CoA binding domain containing 3 (ACBD3), and then resulted in the steatosis resolution. Hepatotoxicity of steatosis-related lipid peroxidation, being characterized by mitochondrial dysfunction, growth arrest, and apoptosis, is resultantly prevented after the circRNA_0046367 administration. These findings indicate a circRNA_0046367/miR-34a/PPARα regulatory system underlying hepatic steatosis. Normalized expression of circRNA_0046367 may ameliorate the lipoxidative stress on the basis of steatosis attenuation. circRNA_0046367, therefore, is suggested to be potential approach to the therapy of lipid peroxidative damage.
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Proinflammatory cytokine MIF plays a role in the pathogenesis of type-2 diabetes mellitus, but does not affect hepatic mitochondrial function. Cytokine 2017; 99:214-224. [PMID: 28780379 DOI: 10.1016/j.cyto.2017.07.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 07/08/2017] [Accepted: 07/13/2017] [Indexed: 02/02/2023]
Abstract
BACKGROUND Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays an important role in the pathogenesis of type 2 diabetes mellitus (T2DM). Although the effect of high glucose on liver function has been described, the role of MIF in hepatic mitochondrial function during T2DM has not been studied. OBJECTIVE We examine the influence of MIF to hepatic mitochondrial function in T2DM mouse model. METHODS WT and Mif-/- BALB/c mice were treated with a single dose of streptozotocin (STZ). After an 8-week follow-up, serum glucose, proinflammatory cytokines, C-reactive protein (CRP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzyme quantification, and liver histological analyses were performed. Liver mitochondria were extracted, and mitochondrial function was evaluated by oximetry, swelling and peroxide production. RESULTS Following treatment with STZ, WT mice (WT/STZ) developed significant hyperglycemia and high serum levels of MIF, tumor necrosis factor (TNF)-α, interleukin-β (IL-β), and CRP. Liver damage enzymes ALT and AST were found at high levels. In contrast, Mif-/-STZ lacked serum MIF levels and showed smaller increases in blood glucose, less TNF-α, IL-1β, CPR, ALT and AST, and failure to develop clinical signs of disease compared to the WT/STZ group. Mitochondria extracted from the Mif-/-STZ liver showed similar respiratory control (RC) to WT/STZ or healthy mice with glutamate/malate or succinate as substrates. The four respiratory chain complexes also had comparable activities. WT/STZ-isolated mitochondria showed low swelling with calcium compared to mitochondria from Mif-/-STZ or healthy mice. Peroxide production was comparable in all groups. CONCLUSION These results show although high systemic levels of MIF contribute to the development of T2DM pathology, the liver mitochondria remain unaltered. Importantly, the absence of MIF reduced the pathology of T2DM, also without altering liver mitochondrial function. These support MIF as a therapeutic target for the treatment of this disease in humans.
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Platelets redox balance assessment: Current evidence and methodological considerations. Vascul Pharmacol 2017; 93-95:6-13. [DOI: 10.1016/j.vph.2017.06.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 05/10/2017] [Accepted: 06/28/2017] [Indexed: 01/22/2023]
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