Lecithin:Cholesterol Acyltransferase (LCAT) Deficiency Promotes Differentiation of Satellite Cells to Brown Adipocytes in a Cholesterol-Dependent Manner [Lipids]

October 22nd, 2015 by Nesan, D., Tavallaee, G., Koh, D., Bashiri, A., Abdin, R., Ng, D. S.

Our lab previously reported that lecithin:cholesterol acyltransferase (LCAT) and LDL receptor double knockout mice (Ldlr-/-xLcat-/- or DKO) spontaneously develop functioning ectopic brown adipose tissue (BAT) in skeletal muscle, putatively contributing to the protection from diet-induced obesity phenotype. Here we further investigated their developmental origin and the mechanistic role of LCAT deficiency. Gene profiling of skeletal muscle in DKO newborns and adults revealed a classical lineage. Primary quiescent satellite cells (SC) from chow-fed DKO mice, not in Ldlr-/-xLcat+/+ single-knockout (SKO) or C57BL/6 wild type, were found to (i) express exclusively classical BAT-selective genes, (ii) be primed to express key functional BAT genes and (iii) exhibit markedly increased ex vivo adipogenic differentiation into brown adipocytes. This gene priming effect was abrogated upon feeding the mice a 2% high cholesterol diet (HCD) in association with accumulation of excess intracellular cholesterol. Ex vivo cholesterol loading of chow-fed DKO SC recapitulated the effect, indicating that cellular cholesterol is a key regulator of SC-to-BAT differentiation. Comparing adipogenicity of Ldlr+/+xLcat-/- (LCAT-KO) SC to those of DKO mice identified a specific role for LCAT deficiency in priming of SC to express BAT genes, and that cellular cholesterol depletion is important for adipogenic differentiation, as evidenced by comparable induction of adipogenesis by depleting cholesterol in SC from both LCAT-KO and SKO mice. Taken together, we conclude that ectopic BAT in DKO cells are classical in origin and their development begins in utero. We further showed complementary roles of LCAT deficiency and cellular cholesterol reduction in the SC-to-BAT adipogenesis.
  • Posted in Journal of Biological Chemistry, Publications
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