Understanding the Role of Exercise in Nonalcoholic Fatty Liver Disease: ERS-Linked Molecular Pathways

Zou, Yong; Qi, Zhengtang

doi:10.1155/2020/6412916

Cited by 18 publications

(14 citation statements)

References 151 publications

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“…To simulate the E167K condition and explore the influence of TM6SF2 on lipid accumulation, we generated TM6SF2-knockdown cells in both the L02 and HepG2 cell lines (Figure 3A ), which were incubated with PA (150 μmol/L) or BSA (fatty acid free) for 24 h. We found that TM6SF2-knockdown cells demonstrated higher levels of intracellular TG (Figure 3B ) and more severe lipid accumulation (Figure 3C ). Lipid overload induces endoplasmic reticulum stress (ERS) and causes cell death[ 28 , 29 ]. The cell viability assay results proved that TM6SF2 knockdown markedly exacerbated PA-induced cell death (Figure 3D ), which reflected the increase in lipid content in the TM6SF2-knockdown group.…”

Section: Resultsmentioning

confidence: 99%

Mechanism and therapeutic strategy of hepatic TM6SF2-deficient non-alcoholic fatty liver diseases via in vivo and in vitro experiments

Li¹,

Wu²,

Qiu³

et al. 2022

WJG

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BACKGROUND The lack of effective pharmacotherapies for nonalcoholic fatty liver disease (NAFLD) is mainly attributed to insufficient research on its pathogenesis. The pathogenesis of TM6SF2-efficient NAFLD remains unclear, resulting in a lack of therapeutic strategies for TM6SF2-deficient patients. AIM To investigate the role of TM6SF2 in fatty acid metabolism in the context of fatty liver and propose possible therapeutic strategies for NAFLD caused by TM6SF2 deficiency. METHODS Liver samples collected from both NAFLD mouse models and human participants (80 cases) were used to evaluate the expression of TM6SF2 by using western blotting, immunohistochemistry, and quantitative polymerase chain reaction. RNA-seq data retrieved from the Gene Expression Omnibus database were used to confirm the over-expression of TM6SF2. Knockdown and overexpression of TM6SF2 were performed to clarify the mechanistic basis of hepatic lipid accumulation in NAFLD. MK-4074 administration was used as a therapeutic intervention to evaluate its effect on NAFLD caused by TM6SF2 deficiency. RESULTS Hepatic TM6SF2 levels were elevated in patients with NAFLD and NAFLD mouse models. TM6SF2 overexpression can reduce hepatic lipid accumulation, suggesting a protective role for TM6SF2 in a high-fat diet (HFD). Downregulation of TM6SF2, simulating the TM6SF2 E167K mutation condition, increases intracellular lipid deposition due to dysregulated fatty acid metabolism and is characterized by enhanced fatty acid uptake and synthesis, accompanied by impaired fatty acid oxidation. Owing to the potential effect of TM6SF2 deficiency on lipid metabolism, the application of an acetyl-CoA carboxylase inhibitor (MK-4074) could reverse the NAFLD phenotypes caused by TM6SF2 deficiency. CONCLUSION TM6SF2 plays a protective role in the HFD condition; its deficiency enhanced hepatic lipid accumulation through dysregulated fatty acid metabolism, and MK-4074 treatment could alleviate the NAFLD phenotypes caused by TM6SF2 deficiency.

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Section: Resultsmentioning

confidence: 99%

Mechanism and therapeutic strategy of hepatic TM6SF2-deficient non-alcoholic fatty liver diseases via in vivo and in vitro experiments

Li¹,

Wu²,

Qiu³

et al. 2022

WJG

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“…Presently, there is no clear conclusion regarding the impact of different exercise methods, exercise intensity, and exercise duration on ER stress intensity and stress duration in different tissues. In an 8-week swimming training study on HFD-fed rats, aerobic exercise is found to significantly reduce ER stress in rat liver tissue and testicular fat [ 47 ]. Three months of aerobic exercise is found to reduce GRP-78, IRE1, and p-eIF2 α mRNA and protein levels in subcutaneous fat tissue and blood mononuclear cells of obese adults [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Curcumin in Combination with Aerobic Exercise Improves Follicular Dysfunction via Inhibition of the Hyperandrogen‐Induced IRE1α/XBP1 Endoplasmic Reticulum Stress Pathway in PCOS‐Like Rats

Zhang

Weng

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Combining diet with exercise can improve health and performance. Exercise can reduce androgen excess and insulin resistance (IR) in polycystic ovary syndrome (PCOS) patients. Curcumin is also presumed to improve the follicle development disorder. Here, we investigated the effects of a combination therapy of oral intake of curcumin and exercise on hyperandrogen-induced endoplasmic reticulum (ER) stress and ovarian granulosa cell (GC) apoptosis in rats with PCOS. We generated a PCOS model via continuous dehydroepiandrosterone subcutaneous injection into the necks of Sprague Dawley rats for 35 days. PCOS-like rats then received curcumin treatment combined with aerobic (treadmill) exercise for 8 weeks. We found that compared to control rats, the ovarian tissue and ovarian GCs of hyperandrogen-induced PCOS rats showed increased levels of ER stress-related genes and proteins. Hyperandrogen-induced ovarian GC apoptosis, which was mediated by excessive ER stress and unfolded protein response (UPR) activation, could cause follicle development disorders. Both curcumin gavage and aerobic exercise improved ovarian function via inhibiting the hyperandrogen-activated ER stress IRE1α-XBP1 pathway. Dihydrotestosterone- (DHT-) induced ER stress was mitigated by curcumin/irisin or 4μ8C (an ER stress inhibitor) in primary GC culture. In this in vitro model, the strongly expressed follicular development-related genes Ar, Cyp11α1, and Cyp19α1 were also downregulated.

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“…However, the current therapeutic outcomes for dealing with NAFLD-related metabolic pathologies are unsatisfactory [ 32 ]. In line with this, exercise has been proposed as an effective treatment strategy for NAFLD through various mechanisms, such as the upregulation of antioxidant enzymes and anti-inflammatory mediators and through the regulation of the endoplasmic reticulum stress-associated pathways [ 33 , 34 ]. In light of these studies, we identified the HFD-induced NAFLD-linked protein expression profile in sedentary and exercise intervention mouse models through a high-throughput quantification of proteins.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of the effect of high-fat-diet and voluntary physical activity on mouse liver

Imdad

et al. 2022

PLoS ONE

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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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Understanding the Role of Exercise in Nonalcoholic Fatty Liver Disease: ERS-Linked Molecular Pathways

Cited by 18 publications

References 151 publications

Mechanism and therapeutic strategy of hepatic TM6SF2-deficient non-alcoholic fatty liver diseases via in vivo and in vitro experiments

Mechanism and therapeutic strategy of hepatic TM6SF2-deficient non-alcoholic fatty liver diseases via in vivo and in vitro experiments

Curcumin in Combination with Aerobic Exercise Improves Follicular Dysfunction via Inhibition of the Hyperandrogen‐Induced IRE1α/XBP1 Endoplasmic Reticulum Stress Pathway in PCOS‐Like Rats

Proteomic analysis of the effect of high-fat-diet and voluntary physical activity on mouse liver

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