Deficiency of an orphan nuclear hormone receptor small heterodimer partner (SHP, NR0B2) protects mice from diet-induced hepatic steatosis via repression of Pparg2 gene expression in part. Alcoholic fatty liver diseases (AFLD) share many common pathophysiological features with non-alcoholic fatty liver diseases (NAFLD). To study the role of SHP and PPARγ2 in AFLD, we challenged wild type (WT) and SHP knockout (SHP-/-) mice with ethanol using chronic plus a single binge feeding strategy. 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 either ethanol or high-fat diet. Interestingly, ethanol-fed SHP-/- mice displayed similar hepatic fat accumulation to 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 Aldh2 mRNA level was higher compared with WT counterparts. Following an intoxicating dose of ethanol administration, 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-/- mice compared to WT mice. The ethanol-induced inflammatory responses and lipid peroxidation were also lower in SHP-/- mice. The current data shows that SHP-/- mice undergo faster ethanol catabolism and store extra fat through conversion of acetate to acetyl-CoA before its release into circulation in this ethanol-feeding model.
- Small Heterodimer Partner
- Alcoholic fatty liver disease
- Acetaldehyde dehydrogenase
- Copyright © 2015, American Journal of Physiology- Gastrointestinal and Liver Physiology