title: Involvement of oxygen-regulated protein 150 in AMP-activated protein kinase-mediated alleviation of lipid-induced endoplasmic reticulum stress.
abstract: Hepatocytes show endoplasmic reticulum (ER) stress when exposed to lipotoxic stimuli such as hyperlipidemia. Recent work has revealed that AMP- activated protein kinase (AMPK) can mitigate ER stress. In this study we investigated the impact of AMPK on lipid-induced ER stress in hepatocytes and its underlying molecular mechanism. Treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK agonist, or overexpression of a constitutively active AMPK significantly suppressed lipid-mediated ER stress, leading to marked protection against lipotoxic death. Incubation with AICAR and constitutively active AMPK overexpression induced the expression of an ER-associated chaperone, 150-kDa oxygen-regulated protein (ORP150), at both the mRNA and protein levels in hepatocytes. Forkhead box O1 (FOXO1) was identified as the critical transcription factor regulating ORP150 expression because silencing FOXO1 expression prevented the induction of ORP150 expression by AMPK. In contrast, overexpression of FOXO1-ADA promoted ORP150 expression in hepatocytes. FOXO1 bound directly to the ORP150 promoter, which was enhanced in the presence of AICAR. AMPK acts to activate FOXO1 by increasing its deacetylation and transcriptional activity via silent mating type information regulation 2 homolog 1 (SIRT1). Furthermore, AICAR infusion enhanced ORP150 expression, resulting in the marked amelioration of hepatic ER stress and apoptosis in C57BL/6J mice fed a high fat diet. Our results reveal a novel mechanism by which AMPK regulates ER homeostasis in hepatocytes and suggest that AMPK has a protective role against hypercholesterolemia-related liver damage.
authors.affiliation: Guangdong Provincial Key Laboratory of Food, Nutrition, and Health, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Wu
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Duan
authors.initials: D
authors.lastname: Wang
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.forename: Xiang
authors.initials: X
authors.lastname: Feng
authors.forename: Min
authors.initials: M
authors.lastname: Xia
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050356:Lipid Metabolism / Q000502:physiology*; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects / Q000502:physiology*
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D018840:HSP70 Heat-Shock Proteins; D007004:Hypoglycemic Agents; D011506:Proteins; D012265:Ribonucleotides; C050087:oxygen-regulated proteins; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C031143:AICA ribonucleotide