title: Enhanced ethanol catabolism in orphan nuclear receptor SHP-null mice.
abstract: Deficiency of the orphan nuclear hormone receptor small heterodimer partner (SHP, NR0B2) protects mice from diet-induced hepatic steatosis, in part, via repression of peroxisome proliferator-activated receptor (PPAR)-γ2 (Pparg2) gene expression. Alcoholic fatty liver diseases (AFLD) share many common pathophysiological features with non-AFLD. To study the role of SHP and PPARγ2 in AFLD, we used a strategy of chronic ethanol feeding plus a single binge ethanol feeding to challenge wild-type (WT) and SHP-null (SHP(-/-)) mice with ethanol. The ethanol feeding induced liver fat accumulation and mRNA expression of hepatic Pparg2 in WT mice, which suggests that a high level of PPARγ2 is a common driving force for fat accumulation induced by ethanol or a high-fat diet. Interestingly, ethanol-fed SHP(-/-) mice displayed hepatic fat accumulation similar to that of ethanol-fed WT mice, even though their Pparg2 expression level remained lower. Mortality of SHP(-/-) mice after ethanol binge feeding was significantly reduced and their acetaldehyde dehydrogenase (Aldh2) mRNA level was higher than that of their WT counterparts. After an intoxicating dose of ethanol, SHP(-/-) mice exhibited faster blood ethanol clearance and earlier wake-up time than WT mice. Higher blood acetate, the end product of ethanol metabolism, and lower acetaldehyde levels were evident in the ethanol-challenged SHP(-/-) than WT mice. Ethanol-induced inflammatory responses and lipid peroxidation were also lower in SHP(-/-) mice. The current data show faster ethanol catabolism and extra fat storage through conversion of acetate to acetyl-CoA before its release into the circulation in this ethanol-feeding model in SHP(-/-) mice.
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Park
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio.
authors.forename: Mikang
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio.
authors.forename: Ryan
authors.initials: R
authors.lastname: Mifflin
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio ylee3@neomed.edu.
authors.forename: Yoon Kwang
authors.initials: YK
authors.lastname: Lee
mesh_terms: D000085:Acetates / Q000097:blood; D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000431:Ethanol / Q000097:blood / Q000378:metabolism* / Q000633:toxicity; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D000085:Acetates; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2; D000431:Ethanol; C515029:ALDH2 protein, mouse; D000071396:Aldehyde Dehydrogenase, Mitochondrial
keywords: acetaldehyde dehydrogenase; alcoholic fatty liver disease; inflammation; small heterodimer partner