Adipocyte GPX4 protects against inflammation, hepatic insulin resistance and metabolic dysregulation

Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). Metabolic dysfunction in this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, with insulin resistance as the common underlying pathophysiology. Imbalance between energy intake and expenditure results in insulin resistance in various tissues and alteration of the gut microbiota, resulting in fat accumulation in the liver. The role of genetics has also been revealed in hepatic fat accumulation and fibrosis. In the process of fat accumulation in the liver, intracellular damage as well as hepatic insulin resistance further potentiates inflammation, fibrosis, and carcinogenesis. Increased lipogenic substrate supply from other tissues, hepatic zonation of Irs1, and other factors, including ER stress, play crucial roles in increased hepatic de novo lipogenesis in MAFLD with hepatic insulin resistance. Herein, we provide an overview of the factors contributing to and the role of systemic and local insulin resistance in the development and progression of MAFLD.

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MicroRNA-191 blocking the translocation of GLUT4 is involved in arsenite-induced hepatic insulin resistance through inhibiting the IRS1/AKT pathway

Ecotoxicology and Environmental Safety ◽

10.1016/j.ecoenv.2021.112130 ◽

2021 ◽

Vol 215 ◽

pp. 112130

Author(s):

Wenqi Li ◽

Lu Wu ◽

Qian Sun ◽

Qianlei Yang ◽

Junchao Xue ◽

...

Keyword(s):

Insulin Resistance ◽

Hepatic Insulin Resistance ◽

Akt Pathway

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Feeding diversified protein sources exacerbates hepatic insulin resistance via increased gut microbial branched-chain fatty acids and mTORC1 signaling in obese mice

Nature Communications ◽

10.1038/s41467-021-23782-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Béatrice S.-Y. Choi ◽

Noëmie Daniel ◽

Vanessa P. Houde ◽

Adia Ouellette ◽

Bruno Marcotte ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Gut Microbiota ◽

Protein Source ◽

Hepatic Insulin Resistance ◽

Branched Chain Fatty Acids ◽

Mtorc1 Signaling ◽

Branched Chain ◽

Mixed Protein ◽

Chain Fatty Acids

AbstractAnimal models of human diseases are classically fed purified diets that contain casein as the unique protein source. We show that provision of a mixed protein source mirroring that found in the western diet exacerbates diet-induced obesity and insulin resistance by potentiating hepatic mTORC1/S6K1 signaling as compared to casein alone. These effects involve alterations in gut microbiota as shown by fecal microbiota transplantation studies. The detrimental impact of the mixed protein source is also linked with early changes in microbial production of branched-chain fatty acids (BCFA) and elevated plasma and hepatic acylcarnitines, indicative of aberrant mitochondrial fatty acid oxidation. We further show that the BCFA, isobutyric and isovaleric acid, increase glucose production and activate mTORC1/S6K1 in hepatocytes. Our findings demonstrate that alteration of dietary protein source exerts a rapid and robust impact on gut microbiota and BCFA with significant consequences for the development of obesity and insulin resistance.

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Caloric Restriction Reverses Hepatic Insulin Resistance and Steatosis in Rats with Low Aerobic Capacity

Endocrinology ◽

10.1210/en.2010-0176 ◽

2010 ◽

Vol 151 (11) ◽

pp. 5157-5164 ◽

Cited By ~ 30

Author(s):

Thomas A. Bowman ◽

Sadeesh K. Ramakrishnan ◽

Meenakshi Kaw ◽

Sang Jun Lee ◽

Payal R. Patel ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Caloric Restriction ◽

Visceral Obesity ◽

Insulin Clearance ◽

Hepatic Insulin Resistance ◽

The Metabolic Syndrome ◽

Cell Adhesion Molecule 1 ◽

Muscle Triglyceride

Rats selectively bred for low aerobic running capacity exhibit the metabolic syndrome, including hyperinsulinemia, insulin resistance, visceral obesity, and dyslipidemia. They also exhibit features of nonalcoholic steatohepatitis, including chicken-wire fibrosis, inflammation, and oxidative stress. Hyperinsulinemia in these rats is associated with impaired hepatic insulin clearance. The current studies aimed to determine whether these metabolic abnormalities could be reversed by caloric restriction (CR). CR by 30% over a period of 2–3 months improved insulin clearance in parallel to inducing the protein content and activation of the carcinoembryonic antigen-related cell adhesion molecule 1, a main player in hepatic insulin extraction. It also reduced glucose and insulin intolerance and serum and tissue (liver and muscle) triglyceride levels. Additionally, CR reversed inflammation, oxidative stress, and fibrosis in liver. The data support a significant role of CR in the normalization of insulin and lipid metabolism in liver.

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Beneficial effect of omarigliptin on diabetic patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis

Diabetology & Metabolic Syndrome ◽

10.1186/s13098-021-00644-5 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Sachiko Hattori ◽

Kazuomi Nomoto ◽

Tomohiko Suzuki ◽

Seishu Hayashi

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Liver Function ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Hepatic Insulin Resistance ◽

Diabetic Patients ◽

Alcoholic Fatty Liver ◽

Dpp4 Inhibitor ◽

Alcoholic Fatty Liver Disease

Abstract Background Dipeptidyl peptidase 4 (DPP4) is a serine exopeptidase able to inactivate various oligopeptides, and also a hepatokine. Hepatocyte-specific overexpression of DPP4 is associated with hepatic insulin resistance and liver steatosis. Method We examined whether weekly DPP4 inhibitor omarigliptin (OMG) can improve liver function as well as levels of inflammation and insulin resistance in type 2 diabetic patients with non-alcoholic fatty liver disease (NAFLD). Further, we investigated the effects of OMG in a diabetic patient with biopsy-confirmed nonalcoholic steatohepatitis (NASH). Results In NAFLD patients, OMG significantly decreased levels of aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hsCRP), while no significant change was seen in hemoglobin A1c or body mass index. In the NASH patient, liver function improved markedly, and levels of the hepatic fibrosis marker FIB-4 decreased in parallel with HOMA-IR and hsCRP. Slight but clear improvements in intrahepatic fat deposition and fibrosis appeared to be seen on diagnostic ultrasonography. Conclusion Weekly administration of the DPP4 inhibitor OMG in ameliorating hepatic insulin resistance may cause beneficial effects in liver with NAFLD/NASH.

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