Metformin Alleviates Hepatic Steatosis and Insulin Resistance in a Mouse Model of High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease by Promoting Transcription Factor EB-Dependent Autophagy

Zhang, Dan; Ma, Yi‐Cheng; Liu, Jianjun; Deng, Yi; Zhou, Bo; Wen, Yu; Li, Mingke; Wen, Daiyan; Ying, Yunyan; Luo, Sufeng; Shi, Chunjing; Pu, Guangyu; Miao, Yi; Zou, Cheng‐Gang; Chen, Yuanli; Ma, Lanqing

doi:10.3389/fphar.2021.689111

Cited by 23 publications

(15 citation statements)

References 55 publications

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“…In MAFLD induced by a high-fat diet, metformin directly decreased fat deposition and inhibited inflammation in the liver by increasing phosphorylation of liver AMPK and ACC but decreased lipogenic enzymes and proinflammatory cytokines [ 84 ]. Furthermore, the reversal effect of metformin on insulin resistance and hepatic steatosis is autophagy-dependent via the transcriptional factor EB, a potent regulator of autophagy [ 85 ]. Although metformin has been documented in some studies to be beneficial in MAFLD and chronic hepatitis C patients [ 86 , 87 ], its use has been inadvisable in patients with cirrhosis due to increased risk of lactic acidosis [ 88 , 89 ].…”

Section: A Mechanistic View Of Therapies For Mafldmentioning

confidence: 99%

Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways

et al. 2022

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The metabolic-associated fatty liver disease (MAFLD) is a condition of fat accumulation in the liver in combination with metabolic dysfunction in the form of overweight or obesity and insulin resistance. It is also associated with an increased cardiovascular disease risk, including hypertension and atherosclerosis. Hepatic lipid metabolism is regulated by a combination of the uptake and export of fatty acids, de novo lipogenesis, and fat utilization by β-oxidation. When the balance between these pathways is altered, hepatic lipid accumulation commences, and long-term activation of inflammatory and fibrotic pathways can progress to worsen the liver disease. This review discusses the details of the molecular mechanisms regulating hepatic lipids and the emerging therapies targeting these pathways as potential future treatments for MAFLD.

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Section: A Mechanistic View Of Therapies For Mafldmentioning

confidence: 99%

Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways

et al. 2022

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“…In T2D, AMPK and SIRT1 signaling is inhibited, whereas metformin and SGLT-2 inhibitors can activate both signals to facilitate autophagy, respectively ( Packer, 2020 ). The therapeutic effect of metformin in autophagy regulation in diabetes is associated with TFEB, which regulates metformin-induced autophagy ( Zhang D et al, 2021 ). MSL, an autophagy enhancer, activates calcineurin and increases the conversion of LC3-I to LC3-II.…”

Section: Effect Of Improved Autophagy On Chronic Complications Of Dia...mentioning

confidence: 99%

Research progress on the relationship between autophagy and chronic complications of diabetes

Wang

Fei

et al. 2022

Front. Physiol.

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Diabetes is a common metabolic disease whose hyperglycemic state can induce diverse complications and even threaten human health and life security. Currently, the treatment of diabetes is restricted to drugs that regulate blood glucose and have certain accompanying side effects. Autophagy, a research hotspot, has been proven to be involved in the occurrence and progression of the chronic complications of diabetes. Autophagy, as an essential organismal defense mechanism, refers to the wrapping of cytoplasmic proteins, broken organelles or pathogens by vesicles, which are then degraded by lysosomes to maintain the stability of the intracellular environment. Here, we review the relevant aspects of autophagy and the molecular mechanisms of autophagy in diabetic chronic complications, and further analyze the impact of improving autophagy on diabetic chronic complications, which will contribute to a new direction for further prevention and treatment of diabetic chronic complications.

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“…The pleiotropic effects of MET are widely acknowledged, but its positive impact on lipid metabolism is debatable. While experimental studies have documented an improvement in lipid management across ectopic lipid deposition and circulating lipids [40], clinical studies are less definitive, with some finding no improvement [13]. In our study, SM enhancement reduced serum TAG and elevated HDL cholesterol (Table 2).…”

Section: Discussionmentioning

confidence: 51%

The Beneficial Additive Effect of Silymarin in Metformin Therapy of Liver Steatosis in a Pre-Diabetic Model

et al. 2021

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The combination of plant-derived compounds with anti-diabetic agents to manage hepatic steatosis closely associated with diabetes mellitus may be a new therapeutic approach. Silymarin, a complex of bioactive substances extracted from Silybum marianum, evinces an antioxidative, anti-inflammatory, and hepatoprotective activity. In this study, we investigated whether metformin (300 mg/kg/day for four weeks) supplemented with micronized silymarin (600 mg/kg/day) would be effective in mitigating fatty liver disturbances in a pre-diabetic model with dyslipidemia. Compared with metformin monotherapy, the metformin–silymarin combination reduced the content of neutral lipids (TAGs) and lipotoxic intermediates (DAGs). Hepatic gene expression of enzymes and transcription factors involved in lipogenesis (Scd-1, Srebp1, Pparγ, and Nr1h) and fatty acid oxidation (Pparα) were positively affected, with hepatic lipid accumulation reducing as a result. Combination therapy also positively influenced arachidonic acid metabolism, including its metabolites (14,15-EET and 20-HETE), mitigating inflammation and oxidative stress. Changes in the gene expression of cytochrome P450 enzymes, particularly Cyp4A, can improve hepatic lipid metabolism and moderate inflammation. All these effects play a significant role in ameliorating insulin resistance, a principal background of liver steatosis closely linked to T2DM. The additive effect of silymarin in metformin therapy can mitigate fatty liver development in the pre-diabetic state and before the onset of diabetes.

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Metformin Alleviates Hepatic Steatosis and Insulin Resistance in a Mouse Model of High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease by Promoting Transcription Factor EB-Dependent Autophagy

Cited by 23 publications

References 55 publications

Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways

Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways

Research progress on the relationship between autophagy and chronic complications of diabetes

The Beneficial Additive Effect of Silymarin in Metformin Therapy of Liver Steatosis in a Pre-Diabetic Model

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