High fat diet disrupts endoplasmic reticulum calcium homeostasis in the rat liver

Wires, Emily S.; Trychta, Kathleen A.; Bäck, Susanne; Sulima, Agnieszka; Rice, Kenner C.; Harvey, Brandon K.

doi:10.1016/j.jhep.2017.05.023

Cited by 47 publications

(28 citation statements)

References 44 publications

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“…Animal models of NAFLD induced by HFD (32,33) have been widely used to examine the pathogenesis of NAFLD and to investigate new treatment strategies (34). HFD-induced liver disease, in contrast with rifampicin-isoniazid-induced hepatotoxicity (35), not only leads to chronic inflammation and liver fibrosis, but also disrupts endoplasmic reticulum calcium homeostasis (36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin promotes AMPK signaling to protect against high fat diet‑induced non‑alcoholic fatty liver in golden hamsters

Zhang

et al. 2020

Exp Ther Med

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Non-alcoholic fatty liver disease (NAFLD) is characterized by diffuse fatty acid degeneration and excess fat accumulation in the liver. Notably, the currently available medications used to treat NAFLD remain limited. The aim of the present study was to investigate the protective role of atorvastatin (Ato) against NAFLD in golden hamsters fed a high fat diet (HFD) and in HepG2 cells treated with palmitate, and identify the underlying molecular mechanism. Ato (3 mg/kg) was administered orally every day for 8 weeks to the hamsters during HFD administration. Hamsters in the model group developed hepatic steatosis with high serum levels of triglyceride, cholesterol, insulin and C-reactive protein, which were effectively reduced by treatment with Ato. Additionally, the relative liver weight of hamsters treated with Ato was markedly lower compared with that of the model group. Hematoxylin and eosin, and oil red O staining indicated that the livers of the animals in the model group exhibited large and numerous lipid droplets, which were markedly decreased after Ato treatment. Western blot analysis indicated that Ato inhibited fat accumulation in the liver through the AMP-activated protein kinase (AMPK)-dependent activation of peroxisome proliferator activated receptor α (PPARα), peroxisome proliferator-activated receptor-γ coactivator 1 α and their target genes. Furthermore, in vitro, Ato inhibited PA-induced lipid accumulation in HepG2 cells. This inhibitory effect was attenuated following Compound C treatment, indicating that AMPK may be a potential target of Ato. In conclusion, the increase in AMPK-mediated PPARα and its target genes may represent a novel molecular mechanism by which Ato prevents NAFLD.

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Section: Discussionmentioning

confidence: 99%

Atorvastatin promotes AMPK signaling to protect against high fat diet‑induced non‑alcoholic fatty liver in golden hamsters

Zhang

et al. 2020

Exp Ther Med

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“…The ER is an organelle important for protein synthesis and folding, lipid synthesis, and Ca 2+ homoeostasis. It is known that palmitate induces ER stress via calcium depletion in the ER [ 17 , 18 ]. Elevated ER stress in the liver could contribute considerably to the alteration of lipid metabolism, thereby leading to hepatic steatosis [ 19 ] and apoptosis [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Dantrolene prevents hepatic steatosis by reducing cytoplasmic Ca2+ level and ER stress

Tamitani

Yamamoto

et al. 2020

Biochemistry and Biophysics Reports

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Introduction Our previous studies demonstrated that dantrolene, a ryanodine receptor stabilizer, prevents endoplasmic reticulum (ER) stress in the heart. ER stress is a strong mediator of impaired lipid metabolism in the liver, thereby contributing to fatty liver disease. In this study, we investigated the effects of dantrolene on fatty liver disease in mice and ER stress in hepatocytes. Methods and results Eight weeks old C57BL/6 mice were fed high-fat diet (HFD) for 8 weeks with or without the oral administration of dantrolene (100 mg/kg/day). The livers of mice without dantrolene (HFD group) showed severe fatty liver, whereas the livers of the mice treated with dantrolene (HFD + DAN group) only showed slightly fatty liver. To address the preventive effects of dantrolene, primary hepatocytes were cultured with palmitate in the presence or absence of dantrolene. Dantrolene reduced lipid load and prevents palmitate-induced increase in cytoplasmic Ca 2+ and ER stress. Based on these findings, we propose that dantrolene is a potential new therapeutic agent against fatty liver disease.

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“…Exercise Reduces Lipid Accumulation in the Liver by Regulating ERS. Lipid ectopic accumulation occurs in the early stage of NAFLD, which leads to ERS in the liver [107]. Unfortunately, ERS further promotes lipid overstore and hepatic steatosis and thus leads to NAFLD [14,108].…”

Section: Ers-related Molecular Mechanism By Whichmentioning

confidence: 99%

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

Zou

2020

Mediators of Inflammation

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Nonalcoholic fatty liver disease (NAFLD) is globally prevalent and characterized by abnormal lipid accumulation in the liver, frequently accompanied by insulin resistance (IR), enhanced hepatic inflammation, and apoptosis. Recent studies showed that endoplasmic reticulum stress (ERS) at the subcellular level underlies these featured pathologies in the development of NAFLD. As an effective treatment, exercise significantly reduces hepatic lipid accumulation and thus alleviates NAFLD. Confusingly, these benefits of exercise are associated with increased or decreased ERS in the liver. Further, the interaction between diet, medication, exercise types, and intensity in ERS regulation is more confusing, though most studies have confirmed the benefits of exercise. In this review, we focus on understanding the role of exercise-modulated ERS in NAFLD and ERS-linked molecular pathways. Moderate ERS is an essential signaling for hepatic lipid homeostasis. Higher ERS may lead to increased inflammation and apoptosis in the liver, while lower ERS may lead to the accumulation of misfolded proteins. Therefore, exercise acts like an igniter or extinguisher to keep ERS at an appropriate level by turning it up or down, which depends on diet, medications, exercise intensity, etc. Exercise not only enhances hepatic tolerance to ERS but also prevents the malignant development of steatosis due to excessive ERS.

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High fat diet disrupts endoplasmic reticulum calcium homeostasis in the rat liver

Cited by 47 publications

References 44 publications

Atorvastatin promotes AMPK signaling to protect against high fat diet‑induced non‑alcoholic fatty liver in golden hamsters

Atorvastatin promotes AMPK signaling to protect against high fat diet‑induced non‑alcoholic fatty liver in golden hamsters

Dantrolene prevents hepatic steatosis by reducing cytoplasmic Ca2+ level and ER stress

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

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