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Betulinic acid alleviates endoplasmic reticulum stress-mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice.

ABSTRACT: BACKGROUND AND PURPOSE:The molecular mechanism for the pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains elusive. Both farnesoid X receptor (FXR) signalling and endoplasmic reticulum (ER) stress contribute to the progression of NAFLD; however, it is not clear whether the actions of these two pathways are dependent on each other. Moreover, the pharmacological benefits and mechanism of betulinic acid (BA) in controlling metabolic syndrome and NAFLD are largely unknown. EXPERIMENTAL APPROACH:A reporter assay and a time-resolved FRET assay were used to identify BA as an agonist of the FXR. NAFLD was induced by a methionine and choline-deficient L-amino acid diet (MCD) and high-fat diet (HFD). The pharmacological effects of BA (100 mg·kg-1 ·day-1 ) and potential interactions between hepatic FXR activation and ER stress pathways were evaluated by FXR silencing, Western blot and RT-PCR analyses using control and FXR-/- mice. KEY RESULTS:Activation of the FXR inhibited intracellular PERK/EIF2?/ATF4 and CHOP signalling, thereby alleviating hepatic ER stress, whereas FXR silencing resulted in an opposite effect. Furthermore, we identified BA as an FXR agonist that effectively attenuated the progression of NAFLD and metabolic disorders in both HFD- and MCD diet-fed mice and restored the hepatocellular ER homeostasis by stimulating the FXR signalling pathway and blocking PERK/EIF2? signalling. In contrast, the effects of BA were attenuated in FXR-/- mice. CONCLUSIONS AND IMPLICATIONS:Our data demonstrate that pharmacological activation of the FXR by BA reduces hepatocellular ER stress and attenuates NAFLD in an animal model of hepatic steatosis.

SUBMITTER: Gu M

PROVIDER: S-EPMC6433649 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Betulinic acid alleviates endoplasmic reticulum stress-mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice.

Gu Ming M Zhao Ping P Zhang Shiying S Fan Shengjie S Yang Li L Tong Qingchun Q Ji Guang G Huang Cheng C

British journal of pharmacology 20190318 7

<h4>Background and purpose</h4>The molecular mechanism for the pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains elusive. Both farnesoid X receptor (FXR) signalling and endoplasmic reticulum (ER) stress contribute to the progression of NAFLD; however, it is not clear whether the actions of these two pathways are dependent on each other. Moreover, the pharmacological benefits and mechanism of betulinic acid (BA) in controlling metabolic syndrome and NAFLD are largely unknown.<h4>Ex ...[more]

PMID: 30635917

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Project description:Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic side effects. The impact of nuclear receptor crosstalk in NAFLD is likely to be profound, but requires further elucidation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

Dataset Information

Betulinic acid alleviates endoplasmic reticulum stress-mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice.

Publications

Betulinic acid alleviates endoplasmic reticulum stress-mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice.

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