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The pivotal role of liver X receptors (LXRs) in the metabolic conversion of cholesterol to bile acids in mice is well established. More recently, the LXRalpha promoter has been shown to be under tight regulation by peroxisome proliferator-activated receptors (PPARs), implying a role for LXRalpha in mediating the interplay between cholesterol and fatty acid metabolism. We have studied the role of LXR in fat cells and demonstrate that LXR is regulated during adipogenesis and augments fat accumulation in mature adipocytes. LXRalpha expression in murine 3T3-L1 adipocytes as well as in human adipocytes was up-regulated in response to PPARgamma agonists. Administration of a PPARgamma agonist to obese Zucker rats also led to increased LXRalpha mRNA expression in adipose tissue in vivo. LXR agonist treatment of differentiating adipocytes led to increased lipid accumulation. An increase of the expression of the LXR target genes, sterol regulatory binding protein-1 and fatty acid synthase, was observed both in vivo and in vitro after treatment with LXR agonists for 24 h. Finally, we demonstrate that fat depots in LXRalpha/beta-deficient mice are smaller than in age-matched wild-type littermates. These findings imply a role for LXR in controlling lipid storage capacity in mature adipocytes and point to an intriguing physiological interplay between LXR and PPARgamma in controlling pathways in lipid handling.

The nuclear receptor liver X receptor (LXR) ␣, an important regulator of cholesterol and bile acid metabolism, was analyzed after insulin stimulation in liver in vitro and in vivo. A time-and dose-dependent increase in LXR␣ steady-state mRNA level was seen after insulin stimulation of primary rat hepatocytes in culture. A maximal induction of 10-fold was obtained when hepatocytes were exposed to 400 nM insulin for 24 h. Cycloheximide, a potent inhibitor of protein synthesis, prevented induction of LXR␣ mRNA expression by insulin, indicating that the induction is dependent on de novo synthesis of proteins. Stabilization studies using actinomycin D indicated that insulin stimulation increased the half-life of LXR␣ transcripts in cultured primary hepatocytes. Complementary studies where rats and mice were injected with insulin induced LXR␣ mRNA levels and confirmed our in vitro studies. Furthermore, deletion of both the LXR␣ and LXR␤ genes (double knockout) in mice markedly suppressed insulin-mediated induction of an entire class of enzymes involved in both fatty acid and cholesterol metabolism. The discovery of insulin regulation of LXR in hepatic tissue as well as gene targeting studies in mice provide strong evidence that LXRs plays a central role not only in cholesterol homeostasis, but also in fatty acid metabolism. Furthermore, LXRs appear to be important insulin-mediating factors in regulation of lipogenesis.Insulin plays a major role in the regulation of carbohydrate and lipid metabolism in the liver, adipose tissue, and muscle. Hepatic fatty acid oxidation, lipogenesis, and glycerolipid synthesis are subject to regulation by insulin (for review, see Ref.

Background-The nature of some of the target genes for liver X receptors (LXRs)-␣ and -␤, such as sterol regulatory element binding protein-1 and ATP-binding cassette transporter proteins, suggests a pivotal role of these nuclear receptors in the regulation of fatty acid and cholesterol homeostasis. The present study aimed to elucidate the physiological relevance of both LXRs with regard to lipid metabolism and macrophage cholesterol efflux. Methods and Results-Mice depleted for LXR␣, LXR␤, or both were fed low-fat rodent chow for 18 months before investigations. The combined deficiency of LXR␣ and LXR␤ was linked to impaired triglyceride metabolism, increased LDL and reduced HDL cholesterol levels, and cholesterol accumulation in macrophages (foam cells) of the spleen, lung, and arterial wall. Conclusions-Our data demonstrate the physiological importance of both LXRs in lipid metabolism and strongly indicate that both LXRs have a protective role against the development of atherosclerosis.

The mechanisms underlying the anti-inflammatory and anti-hypertensive effects of long chain ω-3 polyunsaturated fatty acids (PUFAs) are still unclear. The epoxides of an ω-6 fatty acid, arachidonic acid (epoxyeicosatrienoic acids; EETs) also exhibit anti-hypertensive and anti-inflammatory effects. Thus, we hypothesized that the major ω-3 PUFAs including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may lower blood pressure and attenuate renal markers of inflammation through their epoxide metabolites. Here, we supplemented mice with an ω-3 rich diet for three weeks in a murine model of angiotensin-II dependent hypertension. Also, since EPA and DHA epoxides are metabolized by soluble epoxide hydrolase (sEH), we tested the combination of a sEH inhibitor and the ω-3 rich diet. Our results show that ω-3 rich diet in combination with the sEH inhibitor lowered Ang-II increased blood pressure, further increased renal levels of EPA and DHA epoxides, reduced renal markers of inflammation (i.e. prostaglandins and MCP-1), down-regulated an epithelial sodium channel and up-regulated Angiotensin converting enzyme-2 message (ACE-2) and significantly modulated cyclooxygenase and lipoxygenase metabolic pathways. Overall, our findings suggest that epoxides of the ω-3 PUFAs contribute to lowering SBP and attenuating inflammation in part by reduced prostaglandins and MCP-1 and by up-regulation of ACE-2 in angiotensin-II dependent hypertension.

Liver X receptor (LXR) ␣ and LXR␤ are nuclear oxysterol receptors whose biological function has so far been elucidated only with respect to cholesterol and lipid metabolism.