Atractylenolide I Alleviates Lipotoxicity in Hepatocytes and Protects NAFLD in Mice Through SIRT1-Dependent IRE1α-XBP1 Pathway.

Atractylenolide I (AO-I), a major pharmacological ingredient derived from Atractylodes macrocephala, has been reported to possess multiple bioactivities. This study aimed to investigate the potential protective effects of AO-I against lipotoxicity in both cultured hepatocytes and mice with non-alcoholic fatty liver disease (NAFLD). The NAFLD model was established by feeding C57BL/6 mice a high-fat diet (HFD) for 12 weeks. Oral administration of AO-I at doses of 20 or 50 mg/kg body weight per day was explored. Lipotoxicity in AML12 hepatocytes was induced by incubation with palmitate for in vitro investigations on the roles of AO-I. The results demonstrated that supplementation with AO-I improved alanine transaminase (ALT), aspartate transaminase (AST), and liver histology in NAFLD mice. Furthermore, AO-I directly alleviated palmitate-induced lipotoxicity by reducing hepatocyte death. Mechanistic studies revealed that AO-I significantly attenuated lipotoxicity through its potential resistance to endoplasmic reticulum (ER) stress and IRE1α-XBP1 splicing both in vivo and in vitro. We identified that AO-I substantially rescued HFD- and palmitate-induced SIRT1 decline in mouse livers and hepatocytes, respectively, thereby improving liver injury and hepatocyte cell death. Mechanistic studies demonstrated that the amelioration of ER stress and lipotoxicity by AO-I supplementation depended on SIRT1 activity. Moreover, AO-I also mitigated IRE1α activation-triggered JNK/p38 MAPK hyperphosphorylation. In conclusion, our findings suggest that AO-I exhibits significant therapeutic effects for improving lipotoxicity in the liver and may be considered as a candidate for NAFLD therapy.