Enhanced ethanol catabolism in orphan nuclear receptor SHP-null mice

Am J Physiol Gastrointest Liver Physiol. 2016 May 15;310(10):G799-807. doi: 10.1152/ajpgi.00343.2015. Epub 2016 Mar 11.

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.

Keywords: acetaldehyde dehydrogenase; alcoholic fatty liver disease; inflammation; small heterodimer partner.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetates / blood
  • Aldehyde Dehydrogenase, Mitochondrial / genetics
  • Aldehyde Dehydrogenase, Mitochondrial / metabolism
  • Animals
  • Ethanol / blood
  • Ethanol / metabolism*
  • Ethanol / toxicity
  • Lipid Peroxidation
  • Liver / drug effects
  • Liver / metabolism
  • Liver Diseases, Alcoholic / genetics
  • Liver Diseases, Alcoholic / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Receptors, Cytoplasmic and Nuclear / deficiency
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / metabolism

Substances

  • Acetates
  • PPAR gamma
  • Receptors, Cytoplasmic and Nuclear
  • nuclear receptor subfamily 0, group B, member 2
  • Ethanol
  • ALDH2 protein, mouse
  • Aldehyde Dehydrogenase, Mitochondrial