Betulinic acid alleviates endoplasmic reticulum stress-mediated NAFLD. - GreenMedInfo Summary
Betulinic acid alleviates endoplasmic reticulum stress-mediated NAFLD through activation of FXR in mice.
Br J Pharmacol. 2019 Jan 11. Epub 2019 Jan 11. PMID: 30635917
BACKGROUND AND PURPOSE: The molecular mechanism for the pathogenesis of non-alcoholic 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 (MS) and NAFLD are largely unknown.
EXPERIMENTAL APPROACH: A reporter assay and a time-resolved FRET assay were used to identify BA as a agonist of FXR. NAFLD was induced by methionine and choline-deficient L-amino acid diet (MCD diet) and high-fat diet (HFD) . The pharmacological effects of BA (100 mg.100 gdiet) 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 FXRmice.
KEY RESULTS: We found that the FXR activation inhibited the intracellular PERK/EIF2α/ATF4 and CHOP signalling, thereby alleviating hepatic ER stress, while 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 HF-diet and MCD diet-fed mice and restores thehepatocellular ER homeostasis by stimulating the FXR signalling and blocking PERK/EIF2α signalling. In contrast, the effects of BA were attenuated in FXRmice.
CONCLUSION AND IMPLICATIONS: Our data demonstrate that pharmacological FXR activation by BA reduces hepatocellular ER stress in the treatment of hepatic steatosis.