Liver X receptor preferentially activates de novo lipogenesis in human preadipocytes

Darimont, Christian; Avanti, Ornella; Zbinden, Irène; Leone-Vautravers, Patricia; Mansourian, Robert; Giusti, Vittorio; Macé, Katherine

doi:10.1016/j.biochi.2005.08.010

Cited by 47 publications

(46 citation statements)

References 30 publications

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“…However, the physiological conditions and endogenous signals that activate LXR in fat cells are unknown. Several studies implicate a role of LXR in lipid accumulation in adipocytes (17,19), but we (data not shown) and others (45) have not observed any effects of LXR activation on the expression of genes involved in de novo lipogenesis. Quite contrary, LXR stimulates FA oxidation in human adipocytes (20).…”

Section: Discussioncontrasting

confidence: 57%

“…Both LXR isoforms, LXR␣ and LXR␤ are expressed in human white adipocytes. Expression of LXR␣ is up-regulated during adipocyte differentiation (17,19), levels of LXR␣ are higher in obese patients and SNPs in both LXR isoforms are associated with obesity (21). Data obtained in murine systems indirectly imply that activation of LXR up-regulates the release of FFAs and glycerol from adipocytes (22).…”

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confidence: 99%

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Liver X Receptor (LXR) Regulates Human Adipocyte Lipolysis

Stenson

Rydén

Venteclef

et al. 2011

Journal of Biological Chemistry

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The Liver X receptor (LXR) is an important regulator of carbohydrate and lipid metabolism in humans and mice. We have recently shown that activation of LXR regulates cellular fuel utilization in adipocytes. In contrast, the role of LXR in human adipocyte lipolysis, the major function of human white fat cells, is not clear. In the present study, we stimulated in vitro differentiated human and murine adipocytes with the LXR agonist GW3965 and observed an increase in basal lipolysis. Microarray analysis of human adipocyte mRNA following LXR activation revealed an altered gene expression of several lipolysis-regulating proteins, which was also confirmed by quantitative real-time PCR. We show that expression and intracellular localization of perilipin1 (PLIN1) and hormone-sensitive lipase (HSL) are affected by GW3965. Although LXR activation does not influence phosphorylation status of HSL, HSL activity is required for the lipolytic effect of GW3965. This effect is abolished by PLIN1 knockdown. In addition, we demonstrate that upon activation, LXR binds to the proximal regions of the PLIN1 and HSL promoters. By selective knockdown of either LXR isoform, we show that LXR␣ is the major isoform mediating the lipolysis-related effects of LXR. In conclusion, the present study demonstrates that activation of LXR␣ up-regulates basal human adipocyte lipolysis. This is at least partially mediated through LXR binding to the PLIN1 promoter and down-regulation of PLIN1 expression.Obesity and its associated insulin resistance are important risk factors for type 2 diabetes and cardiovascular disease. Adipose tissue is the main organ for energy storage and release. During adipocyte lipolysis triglycerides (TGs) 2 are hydrolyzed into free fatty acids (FFAs) and glycerol (1). It is well established that spontaneous (basal) lipolysis is increased in obesity and that the ensuing increment in circulating FFAs promotes insulin resistance and type 2 diabetes via several mechanisms (2). Hydrolysis of adipocyte TGs is regulated by two lipases: adipose triglyceride lipase (ATGL) and the tri/ diglyceride lipase hormone-sensitive lipase (HSL) (1). Activity of HSL is regulated by phosphorylation on several serine residues (3). Lipolytic activity of ATGL requires the presence of the cofactor Comparative Gene Identification 58 (CGI-58).Together, HSL and ATGL are responsible for more than 95% of the TG hydrolysis in murine white adipose tissue (WAT) (4). However, the respective role of ATGL and HSL in the regulation of basal and catecholamine-stimulated lipolysis in human adipocytes is not quite clear (5, 6). Besides lipases, the lipid droplet-coating proteins are also known important regulators of lipolysis (3). The most essential group is the perilipin (PLIN) family. The phosphoprotein PLIN1 is the most abundant lipid droplet-coating protein in adipocytes (7). In the basal, unphosphorylated state, PLIN1 inhibits TG breakdown by restricting the access of lipases to the lipid droplet, thereby keeping basal lipolysis at a low level (8,9). Low PLIN1...

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Section: Discussioncontrasting

confidence: 57%

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confidence: 99%

Liver X Receptor (LXR) Regulates Human Adipocyte Lipolysis

Stenson

Rydén

Venteclef

et al. 2011

Journal of Biological Chemistry

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“…SCD-1 catalyzes the desaturation of saturated fatty acyl-CoAs and is regulated by liver X receptor (LXR) (33). LXR gene expression, however, was not different in SMLPL Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

Skeletal Muscle–Specific Deletion of Lipoprotein Lipase Enhances Insulin Signaling in Skeletal Muscle but Causes Insulin Resistance in Liver and Other Tissues

et al. 2008

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OBJECTIVE-Skeletal muscle-specific LPL knockout mouse (SMLPL Ϫ/Ϫ ) were created to study the systemic impact of reduced lipoprotein lipid delivery in skeletal muscle on insulin sensitivity, body weight, and composition. RESEARCH DESIGN AND METHODS-Tissue-specific insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp and 2-deoxyglucose uptake. Gene expression and insulinsignaling molecules were compared in skeletal muscle and liver of SMLPL Ϫ/Ϫ and control mice.RESULTS-Nine-week-old SMLPL Ϫ/Ϫ mice showed no differences in body weight, fat mass, or whole-body insulin sensitivity, but older SMLPL Ϫ/Ϫ mice had greater weight gain and whole-body insulin resistance. High-fat diet feeding accelerated the development of obesity. In young SMLPL Ϫ/Ϫ mice, insulin-stimulated glucose uptake was increased 58% in the skeletal muscle, but was reduced in white adipose tissue (WAT) and heart. Insulin action was also diminished in liver: 40% suppression of hepatic glucose production in SMLPL Ϫ/Ϫ vs. 90% in control mice. Skeletal muscle triglyceride was 38% lower, and insulin-stimulated phosphorylated Akt (Ser473) was twofold greater in SMLPL Ϫ/Ϫ mice without changes in IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase activity. Hepatic triglyceride and liver X receptor, carbohydrate response element-binding protein, and PEPCK mRNAs were unaffected in SMLPL Ϫ/Ϫ mice, but peroxisome proliferator-activated receptor (PPAR)-␥ coactivator-1␣ and interleukin-1␤ mRNAs were higher, and stearoyl-coenzyme A desaturase-1 and PPAR␥ mRNAs were reduced. CONCLUSIONS-LPL deletion in skeletal muscle reduces lipid storage and increases insulin signaling in skeletal muscle without changes in body composition. Moreover, lack of LPL in skeletal muscle results in insulin resistance in other key metabolic tissues and ultimately leads to obesity and systemic insulin resistance. Diabetes 58:116-124, 2009 L ipoprotein lipase (LPL) (European Commission no. 3.1.1.34) is a key enzyme in lipid metabolism and is described as a "gatekeeper" for its role in partitioning lipoprotein-derived free fatty acids (FFAs) between tissues (1). Once hydrolyzed, the lipoprotein-derived FFAs are available for uptake and use by extrahepatic tissues for either storage or oxidation. LPL is most abundant in heart, adipose tissue, and skeletal muscle (2,3). The importance of LPL in fuel partitioning and utilization is underscored by observations that tissuespecific perturbations in LPL activity result in dramatic shifts in body composition and lipid and glucose metabolism (4), particularly in heart and skeletal muscle.We and others previously showed that mice with musclespecific lipoprotein lipase overexpression are insulin resistant (5,6). Insulin resistance developed selectively in muscle, while insulin sensitivity in the liver was not affected. Overexpression of LPL in the skeletal muscle also led to excessive intramyocellular lipid deposition, suggestive of the relationship between lipid storage and insulin sensitivity.To further investigate...

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“…The SREBP1 antibody was produced by LabFrontier using 1-403 construct of SREBP1c as an immunogen. The results were visualized hepatic steatosis and hypertriglyceridemia through the enhancement of de novo fatty acid synthesis, which is accomplished by the induction of key lipogenic genes, such as SREBP1c and FAS (10)(11)(12). Furthermore, it has been reported that chronic activation of LXR contributes to lipotoxicity and apoptosis in pancreatic ␤ -cells through hyperactivation of lipogenesis ( 13 ).…”

Section: Protein Isolation and Western Blottingmentioning

confidence: 98%