ZFIN ID: ZDB-PUB-131021-12
Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice
Karanth, S., Tran, V.M., Kuberan, B., and Schlegel, A.
Date: 2013
Source: Disease models & mechanisms   6(6): 1365-77 (Journal)
Registered Authors: Karanth, Santhosh, Schlegel, Amnon
Keywords: none
MeSH Terms:
  • Animals
  • Cholesterol/biosynthesis*
  • Coenzyme A/metabolism*
  • Diet, Ketogenic/adverse effects
  • Fatty Acids, Unsaturated/metabolism*
  • Fatty Liver/etiology
  • Fish Oils/administration & dosage
  • Mice
  • Zebrafish/metabolism*
PubMed: 24057001 Full text @ Dis. Model. Mech.

Lipid disorders pose therapeutic challenges. Previously we discovered that mutation of the hepatocyte β-hydroxybutyrate transporter Slc16a6a in zebrafish causes hepatic steatosis during fasting marked by increased hepatic triacylglycerol, but not in cholesterol. This selective diversion of trapped ketogenic carbon atoms is surprising because acetate and acetoacetate can exit mitochondria and can be incorporated into both fatty acids and cholesterol in normal hepatocytes. To elucidate the mechanism of this selective diversion of carbon atoms to fatty acids, we fed wildtype and slc16a6a mutant animals high-protein ketogenic diets. We find that slc16a6a mutants have decreased activity of the rate-limiting enzyme of cholesterol biosynthesis 3-hydroxy-3-methylglutaryl-Coenzyme A (Hmgcr), despite increased Hmgcr protein abundance and relative incorporation of mevalonate into cholesterol. These observations suggest the presence of an endogenous Hmgcr inhibitor. We took a candidate approach to identify such inhibitors. First, we found that mutant livers accumulate multiple poly-unsaturated fatty acids (PUFAs) and PUFA-CoAs, and we showed that human HMGCR is inhibited by PUFA-CoAs in vitro. Second, we injected mice with the PUFA eicosapentaenoic acid and observed an acute decrease in hepatic Hmgcr activity, without alteration in Hmgcr protein abundance. These results elucidate a mechanism for PUFA-mediated cholesterol lowering through direct inhibition of Hmgcr.