Unfolded Protein Response Sensors in Hepatic Lipid Metabolism and Nonalcoholic Fatty Liver Disease

Henkel, Anne S.

doi:10.1055/s-0038-1670677

Cited by 27 publications

(20 citation statements)

References 158 publications

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“…Under unstressed conditions, IRE1, PERK, and ATF6 are associated with GRP78 and remain inactive. Upon ER stress, GRP78 dissociates from these sensor proteins, and further actives PERK and IRE1, and regulates intramembrane proteolysis of ATF6 (As, 2018). In this study, after 4 weeks of PA administration, the increased levels of ROS and MDA were markedly decreased in HFD-fed rats.…”

Section: Discussionmentioning

confidence: 99%

“…Very low-density lipoprotein (VLDL) metabolism is considered as a beneficial factor in overcoming the excess formation of triglyceride (TG) and regulating intrahepatic and plasma lipid homeostasis. A dysregulation in VLDL uptake, export, or synthesis is one of the major causes of hepatic steatosis (As, 2018). Current studies have demonstrated that endoplasmic reticulum (ER) stress is implicated in the inhibition of VLDL metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Protective Effect of Patchouli Alcohol Against High-Fat Diet Induced Hepatic Steatosis by Alleviating Endoplasmic Reticulum Stress and Regulating VLDL Metabolism in Rats

et al. 2019

Front. Pharmacol.

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Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic hepatic disorder worldwide. The earliest stage of NAFLD is simple steatosis, which is characterized by the accumulation of triglycerides in hepatocytes. Inhibition of steatosis is a potential treatment for NAFLD. Patchouli alcohol (PA) is an active component of Pogostemon cablin (Blanco) Benth. (Labiatae), which is a medicinal food in Asia countries and proved to possess hepatoprotective effect. This research aimed to investigate the effectiveness of PA against high fat diet (HFD)-induced hepatic steatosis in rats. In this study, male Sprague Dawley rats were fed a HFD for 4 weeks to induce NAFLD. Oral administration with PA significantly reduced pathological severity of steatosis in HFD-fed rats. It was associated with suppressing endoplasmic reticulum (ER) stress and regulating very low-density lipoprotein (VLDL) metabolism. Our data showed that PA treatment effectively attenuated ER stress by inhibiting the activation of protein kinase-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), and activating transcription factor 6 (ATF6). Moreover, PA decreased hepatic VLDL uptake by suppressing very low-density lipoprotein receptor (VLDLR) expression. It also restored VLDL synthesis and export by increasing apolipoprotein B100 (apoB 100) secretion and microsomal triglyceride-transfer protein (MTP) activity. Taken together, PA exerted a protective effect on the treatment of NAFLD in HFD-fed rats and may be potential therapeutic agent acting on hepatic steatosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protective Effect of Patchouli Alcohol Against High-Fat Diet Induced Hepatic Steatosis by Alleviating Endoplasmic Reticulum Stress and Regulating VLDL Metabolism in Rats

et al. 2019

Front. Pharmacol.

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“…Hepatic ER stress, induced by pharmacological agents or metabolic dysregulation, promotes hepatic lipid accumulation by increasing lipogenesis (32). Genetic ablation studies revealed that the phosphorylation of eIF2α, a key downstream target of PERK, exacerbates the progression of hepatic steatosis in mice subjected to pharmacologically induced ER stress (33).…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin suppresses hepatic steatosis and obesity by inhibiting endoplasmic reticulum stress and upregulating fibroblast growth factor 21

Hong

Zhang

et al. 2019

Int J Mol Med

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Erythropoietin (EPO), known primarily for its role in erythropoiesis, was recently reported to play a beneficial role in regulating lipid metabolism; however, the underlying mechanism through which EPO decreases hepatic lipid accumulation requires further investigation. Endoplasmic reticulum (ER) stress may contribute to the progression of hepatic steatosis. The present study investigated the effects of EPO on regulating ER stress in fatty liver. It was demonstrated that EPO inhibited hepatic ER stress and steatosis in vivo and in vitro. Interestingly, these beneficial effects were abrogated in liver-specific sirtuin 1 (SIRT1)-knockout mice compared with wild-type littermates. In addition, in palmitate-treated hepatocytes, small interfering RNA-mediated SIRT1 silencing suppressed the effects of EPO on lipid-induced ER stress. Additionally, EPO stimulated hepatic fibroblast growth factor 21 (FGF21) expression and secretion in a SIRT1-dependent manner in mice. Furthermore, the sensitivity of hepatocytes from obese mice to FGF21 was restored following treatment with EPO. collectively, the results of the present study revealed a new mechanism underlying the regulation of hepatic ER stress and FGF21 expression induced by EPO; thus, EPO may be considered as a potential therapeutic agent for the treatment of fatty liver and obesity.

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“…[7][8][9]21 Although the association between metabolic disease and induction of PAI-1 is well-established, the mechanism by which metabolic derangements induce PAI-1 is unknown. Given that induction of hepatic ER stress is a well-recognized feature of NASH, 22 we considered whether ER stress contributes to the characteristic induction of PAI-1 in NASH. Therefore, in the present study we aim to (a) determine the role of ER stress in the regulation of hepatic Pai-1 expression and (b) determine whether induction of Pai-1 in a murine model of steatohepatitis is regulated by ER stress.…”

mentioning

confidence: 99%

Endoplasmic reticulum stress induces hepatic plasminogen activator inhibitor 1 in murine nonalcoholic steatohepatitis

Olivares

Henkel

2020

FASEB BioAdvances

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The endoplasmic reticulum (ER) functions to maintain protein homeostasis by regulating protein synthesis, folding and processing. Normal ER protein folding capacity can become impaired in response to various types of cellular stress, collectively termed "ER stress". 1 The resulting accumulation of unfolded or misfolded proteins triggers a highly evolutionarily conserved intracellular signal transduction pathway known as the unfolded protein response

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Unfolded Protein Response Sensors in Hepatic Lipid Metabolism and Nonalcoholic Fatty Liver Disease

Cited by 27 publications

References 158 publications

Protective Effect of Patchouli Alcohol Against High-Fat Diet Induced Hepatic Steatosis by Alleviating Endoplasmic Reticulum Stress and Regulating VLDL Metabolism in Rats

Protective Effect of Patchouli Alcohol Against High-Fat Diet Induced Hepatic Steatosis by Alleviating Endoplasmic Reticulum Stress and Regulating VLDL Metabolism in Rats

Erythropoietin suppresses hepatic steatosis and obesity by inhibiting endoplasmic reticulum stress and upregulating fibroblast growth factor 21

Endoplasmic reticulum stress induces hepatic plasminogen activator inhibitor 1 in murine nonalcoholic steatohepatitis

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