LXRβ is the dominant LXR subtype in skeletal muscle regulating lipogenesis and cholesterol efflux

Abstract

Liver X receptors (LXRs) are important regulators of cholesterol, lipid, and glucose metabolism and have been extensively studied in liver, macrophages, and adipose tissue. However, their role in skeletal muscle is poorly studied and the functional role of each of the LXRalpha and LXRbeta subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild-type (WT) and LXRalpha and LXRbeta knockout (KO) mice were established. The present study showed that treatment with the LXR agonist T0901317 increased lipogenesis and apoA1-dependent cholesterol efflux in LXRalpha KO and WT myotubes but not in LXRbeta KO cells. The functional studies were confirmed by T0901317-induced increase in mRNA levels of LXR target genes involved in lipid and cholesterol metabolism in myotubes established from WT and LXRalpha KO mice, whereas only minor changes were observed for these genes in myotubes from LXRbeta KO mice. Gene expression analysis using microarrays showed that very few genes other than the classical, well-known LXR target genes were regulated by LXR in skeletal muscle. The present study also showed that basal glucose uptake was increased in LXRbeta KO myotubes compared with WT myotubes, suggesting a role for LXRbeta in glucose metabolism in skeletal muscle. In conclusion, LXRbeta seems to be the main LXR subtype regulating lipogenesis and cholesterol efflux in skeletal muscle.

LXR Agonist T0901317-Induced Hyperlipidemia Does Not Lead to Lipid Accumulation in the Rat Heart

“…Our data obtained previously indicate also that in rat skeletal muscles LXRβ expression is higher than LXRα [27]. Others reported that LXRβ is the dominant isoform in the heart and skeletal muscle of mice [2,8,28] and in human skeletal muscle [29,30]. …”

“…Similar observation for murine heart was reported by Lei et al [8] where mRNA expression of both LXR isoforms was unchanged after GW3965 injections. Treatment with T0901317 did not affect the expression levels of LXRα and LXRβ also in the mouse myotubes [28,31]. It has been shown that LXRα expression is controlled by an autoregulatory mechanism and synthetic as well as natural LXR agonists increased LXRα expression in human macrophages, adipocytes, hepatocytes, skin fibroblasts and myotubes [30,32,33,34,35,36].…”

“…ApoB secretion prevented cardiac triacylglycerols accumulation in fat-fed transgenic mice with overexpression of human apoB in the heart [57,58]. In mice T0901317 stimulate, both in vivo and in vitro , the expression of apolipoprotein E in skeletal muscles [28], apolipoprotein D in adipocytes [59], apolipoprotein A-IV in hepatocytes [60]. In hamsters T0901317 led to increased plasma triglyceride apoB, due to enhanced hepatic secretion of apoB-containing lipoproteins [61].…”

Liver X receptors as regulators of metabolism

“…In human myotubes, chronic treatment with T0901317 increases cellular uptake of palmitate as well as cellular uncoupling in both control and T2D patients (76). In line with Muscat et al, we and others demonstrated that chronic LXR activation in vivo for 5 weeks reduced cholesterol content in mouse SM (1,77). We established that this reduction appeared in WT, LXRα KO, and LXRβ KO mice, indicating that both isoforms play a major role in RCT in SM.…”

Liver X Receptor Agonist TO901317 Prevents Diacylglycerols Accumulation in the Heart of Streptozotocin-Diabetic Rats

“…We have previously found that TO901317 decreases content of free cholesterol in rat skeletal muscles [33], however, not in the myocardium [11]. TO901317 also increased cholesterol efflux in mice myotubes [34,35], and according to Hessvik et al [35] LXRβ plays the dominant role in this process in skeletal muscle. Recently our group showed that LXRβ is more abundant than LXRα in the rat heart [11], and we speculate that decrease of free cholesterol level observed in the present study was caused mainly by LXRβ activation.…”