This Article Full Text Full Text (PDF) Supplemental Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Google Scholar Articles by Stenson, B. M. Articles by Laurencikiene, J. PubMed PubMed Citation Articles by Stenson, B. M. Articles by Laurencikiene, J.

Activation of Liver X Receptor Regulates Substrate Oxidation in White Adipocytes

Karolinska Institutet, Departments of Medicine (B.M.S., M.R., K.W., A.T.P., J.W.J., P.A., J.L.) and Bionutrition (K.R.S.), Huddinge, SE-141 86 Stockholm, Sweden

Address all correspondence and requests for reprints to: Britta M. Stenson, Karolinska Institutet, Department of Medicine, Lipid Laboratory, Neuroventenskap, Novum, Huddinge, Hälsovägen 7, SE-141 86 Stockholm, Sweden. E-mail: britta.stenson{at}ki.se.

Liver X receptors (LXRs) are nuclear receptors with established roles in cholesterol, lipid, and carbohydrate metabolism, although their function in adipocytes is not well characterized. Increased adipose tissue mass in obesity is associated with increased adipocyte lipolysis. Fatty acids (FA) generated by lipolysis can be oxidized by mitochondrial β-oxidation, reesterified, or released from the adipocyte. The latter results in higher circulating levels of free FAs, in turn causing obesity-related metabolic complications. However, mitochondrial β-oxidation can at least in part counteract an increased output of FA into circulation. In this study, we provide evidence that activation of LXRs up-regulates mitochondrial β-oxidation in both human and murine white adipocytes. We also show that the expression of a kinase regulating the cellular fuel switch, pyruvate dehydrogenase kinase 4 (PDK4), is up-regulated by the LXR agonist GW3965 in both in vitro differentiated human primary adipocytes and differentiated murine 3T3-L1 cells. Moreover, activation of LXR causes PDK4-dependent phosphorylation of the pyruvate dehydrogenase complex, thereby decreasing its activity and attenuating glucose oxidation. The specificity of the GW3965 effect on oxidation was confirmed by RNA interference targeting LXRs. We propose that LXR has an important role in the regulation of substrate oxidation and the switch between lipids and carbohydrates as cellular fuel in both human and murine white adipocytes.