Metabolic adaptation allows Amacr-deficient mice to remain symptom-free despite low levels of mature bile acids

Biochim Biophys Acta. 2013 Aug;1831(8):1335-43. doi: 10.1016/j.bbalip.2013.05.002. Epub 2013 May 13.

Abstract

Bile acids play multiple roles in the physiology of vertebrates; they facilitate lipid absorption, serve as signaling molecules to control carbohydrate and lipid metabolism, and provide a disposal route for cholesterol. Unexpectedly, the α-methylacyl-CoA racemase (Amacr) deficient mice, which are unable to complete the peroxisomal cleavage of C27-precursors to the mature C24-bile acids, are physiologically asymptomatic when maintained on a standard laboratory diet. The aim of this study was to uncover the underlying adaptive mechanism with special reference to cholesterol and bile acid metabolism that allows these mice to have a normal life span. Intestinal cholesterol absorption in Amacr-/- mice is decreased resulting in a 2-fold increase in daily cholesterol excretion. Also fecal excretion of bile acids (mainly C27-sterols) is enhanced 3-fold. However, the body cholesterol pool remains unchanged, although Amacr-deficiency accelerates hepatic sterol synthesis 5-fold. Changes in lipoprotein profiles are mainly due to decreased phospholipid transfer protein activity. Thus Amacr-deficient mice provide a unique example of metabolic regulation, which allows them to have a normal lifespan in spite of the disruption of a major metabolic pathway. This metabolic adjustment can be mainly explained by setting cholesterol and bile acid metabolism to a new balanced level in the Amacr-deficient mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / genetics
  • Bile Acids and Salts / metabolism*
  • Cholesterol / genetics
  • Cholesterol / metabolism*
  • Lipid Metabolism / physiology*
  • Liver / metabolism*
  • Longevity / physiology
  • Mice
  • Mice, Knockout
  • Racemases and Epimerases / genetics
  • Racemases and Epimerases / metabolism*

Substances

  • Bile Acids and Salts
  • Cholesterol
  • Racemases and Epimerases
  • alpha-methylacyl-CoA racemase