PPARgamma regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1 (original) (raw)
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PPARγ regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1
Journal of Clinical Investigation, 2005
In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentrations of cholesterol and triglycerides are strongly correlated in the adipocyte, but little is known about mechanisms regulating cholesterol metabolism in fat cells. Here we report that antidiabetic thiazolidinediones (TZDs) and other ligands for the nuclear receptor PPARγ dramatically upregulate oxidized LDL receptor 1 (OLR1) in adipocytes by facilitating the exchange of coactivators for corepressors on the OLR1 gene in cultured mouse adipocytes. TZDs markedly stimulate the uptake of oxidized LDL (oxLDL) into adipocytes, and this requires OLR1. Increased OLR1 expression, resulting either from TZD treatment or adenoviral gene delivery, significantly augments adipocyte cholesterol content and enhances fatty acid uptake. OLR1 expression in white adipose tissue is increased in obesity and is further induced by PPARγ ligand treatment in vivo. Serum oxLDL levels are decreased in both lean and obese diabetic animals treated with TZDs. These data identify OLR1 as a novel PPARγ target gene in adipocytes. While the physiological role of adipose tissue in cholesterol and oxLDL metabolism remains to be established, the induction of OLR1 is a potential means by which PPARγ ligands regulate lipid metabolism and insulin sensitivity in adipocytes.
PPARgamma regulates adipose triglyceride lipase in adipocytes in vitro and in vivo
American journal of physiology. Endocrinology and metabolism, 2007
Peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates adipocyte genes involved in adipogenesis and lipid metabolism and is the molecular target for thiazolidinedione (TZD) antidiabetic agents. Adipose triglyceride lipase (ATGL) is a recently described triglyceride-specific lipase that is induced during adipogenesis and remains highly expressed in mature adipocytes. This study evaluates the ability of PPARgamma to directly regulate ATGL expression in adipocytes in vitro and in vivo. In fully differentiated 3T3-L1 adipocytes, ATGL mRNA and protein are increased by TZD and non-TZD PPARgamma agonists in a dose- and time-dependent manner. Rosiglitazone-mediated induction of ATGL mRNA is rapid and is not inhibited by the protein synthesis inhibitor cycloheximide, indicating that intervening protein synthesis is not required for this effect. Rosiglitazone-mediated induction of ATGL mRNA and protein is inhibited by the PPARgamma-specific antagonist GW-9662 and is also signi...
PPARγ-Independent Increase in Glucose Uptake and Adiponectin Abundance in Fat Cells
Endocrinology, 2011
Although thiazolidinediones (TZD) effectively improve hyperglycemia and increase adiponectin, a proinsulin-sensitizing adipokine, they also increase adipogenesis via peroxisome proliferator-activated receptor (PPAR)γ induction, which may be undesirable. Recent safety concerns about some TZD have prompted the search for next generation agents that can enhance glycemic control and adiponectin independent of PPARγ or adipogenesis. Reminiscent of TZD action, a human adenovirus, adenovirus 36 (Ad36), up-regulates PPARγ, induces adipogenesis, and improves systemic glycemic control in vivo. We determined whether this effect of Ad36 requires PPARγ and/or adipogenesis. Glucose uptake and relevant cell signaling were determined in mock-infected or human adenoviruses Ad36 or Ad2-infected cell types under the following conditions: 1) undifferentiated human-adipose-tissue-derived stem cells (hASC), 2) hASC differentiated as adipocytes, 3) hASC in presence or absence of a PPARγ inhibitor, 4) NIH/...
PPAR regulates adipose triglyceride lipase in adipocytes in vitro and in vivo
AJP: Endocrinology and Metabolism, 2007
Peroxisome proliferator-activated receptor-γ (PPARγ) regulates adipocyte genes involved in adipogenesis and lipid metabolism and is the molecular target for thiazolidinedione (TZD) antidiabetic agents. Adipose triglyceride lipase (ATGL) is a recently described triglyceride-specific lipase that is induced during adipogenesis and remains highly expressed in mature adipocytes. This study evaluates the ability of PPARγ to directly regulate ATGL expression in adipocytes in vitro and in vivo. In fully differentiated 3T3-L1 adipocytes, ATGL mRNA and protein are increased by TZD and non-TZD PPARγ agonists in a dose-and time-dependent manner. Rosiglitazone-mediated induction of ATGL mRNA is rapid and is not inhibited by the protein synthesis inhibitor cycloheximide, indicating that intervening protein synthesis is not required for this effect. Rosiglitazone-mediated induction of ATGL mRNA and protein is inhibited by the PPARγ-specific antagonist GW-9662 and is also significantly reduced following siRNA-mediated knockdown of PPARγ, supporting the direct transcriptional regulation of ATGL by PPARγ. In vivo, ATGL mRNA and protein are increased by rosiglitazone treatment in white and brown adipose tissue of mice with and without obesity due to high-fat diet or leptin deficiency. Thus, PPARγ positively regulates ATGL mRNA and protein expression in mature adipocytes in vitro and in adipose tissue in vivo, suggesting a role for ATGL in mediating PPARγ's effects on lipid metabolism.
2021
Insulin resistance and obesity are pivotal features of type 2 diabetes mellitus. Peroxisome proliferator-activated receptor γ (PPARγ) is a master transcriptional regulator of systemic insulin sensitivity and energy balance. The anti-diabetic drug thiazolidinediones are potent synthetic PPARγ ligands and insulin sensitizers with undesirable side effects including increased adiposity, fluid retention, and osteoporosis, which limit their clinical use. We and others have proved that 15-keto-PGE2 is an endogenous natural PPARγ ligand. 15-keto-PGE2 is catalyzed by prostaglandin reductase 2 (PTGR2) to become inactive metabolites. We found that 15-keto-PGE2 level is increased in Ptgr2 knockout mice. Ptgr2 knockout mice were protected from diet-induced obesity, insulin resistance, and hepatic steatosis without fluid retention nor reduced bone mineral density. Diet-induced obese mice have drastically reduced 15-keto-PGE2 levels compared to lean mice. Administration of 15-keto-PGE2 markedly im...
Activation of PPARδ alters lipid metabolism in db/db mice
FEBS Letters, 2000
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which heterodimerize with the retinoid X receptor and bind to peroxisome proliferator response elements in the promoters of regulated genes. Despite the wealth of information available on the function of PPARK K and PPARQ Q, relatively little is known about the most widely expressed PPAR subtype, PPARN N. Here we show that treatment of insulin resistant db/db mice with the PPARN N agonist L-165 041, at doses that had no effect on either glucose or triglycerides, raised total plasma cholesterol concentrations. The increased cholesterol was primarily associated with high density lipoprotein (HDL) particles, as shown by fast protein liquid chromatography analysis. These data were corroborated by the chemical analysis of the lipoproteins isolated by ultracentrifugation, demonstrating that treatment with L-165 041 produced an increase in circulating HDL without major changes in very low or low density lipoproteins. White adipose tissue lipoprotein lipase activity was reduced following treatment with the PPARN N ligand, but was increased by a PPARQ Q agonist. These data suggest both that PPARN N is involved in the regulation of cholesterol metabolism in db/db mice and that PPARN N ligands could potentially have therapeutic value.
PPARα controlling HDL metabolism and atherosclerosis
International Congress Series, 2004
Low serum high-density lipoprotein (HDL) cholesterol concentrations are a feature of the metabolic syndrome that is increasingly being recognized as an important risk factor for cardiovascular disease. HDL is a key mediator of reverse cholesterol transport (RCT), a pathway transporting cholesterol from extrahepatic cells and tissues to the liver for excretion. HDL metabolism is controlled by the interaction of its protein constituents, the apolipoproteins, such as apoA-I and apoA-II, with different enzymes (LCAT, HL, LPL), transfer proteins (CETP, PLTP,.. .) and lipoprotein receptors (ABCA-1, SR-BI,.. .). The level of expression of most of these proteins is partly controlled at the level of transcription by transcription factors, among which are the nuclear receptors. Nuclear receptors are activated by small lipophilic signalling molecules. Among these nuclear receptors, peroxisome proliferator-activated receptors were first identified to play a role in the control of lipid metabolism. In this paper, we will focus on the role of PPARa in HDL metabolism, its molecular action mechanism and its potential as pharmacological targets for future drug discovery.
Thiazolidinediones Upregulate Fatty Acid Uptake and Oxidation in Adipose Tissue of Diabetic Patients
Diabetes, 2005
Thiazolidinediones (TZDs) are a new class of insulinsensitizing drugs. To explore how and in which tissues they improve insulin action, we obtained fat and muscle biopsies from eight patients with type 2 diabetes before and 2 months after treatment with rosiglitazone (n ؍ 5) or troglitazone (n ؍ 3). TZD treatment was associated with a coordinated upregulation in the expression of genes and synthesis of proteins involved in fatty acid uptake, binding, -oxidation and electron transport, and oxidative phosphorylation in subcutaneous fat but not in skeletal muscle. These changes were accompanied by a 13% increase in total body fat oxidation, a 20% decrease in plasma free fatty acid levels, and a 46% increase in insulin-stimulated glucose uptake. We conclude that TZDs induced a coordinated stimulation of fatty acid uptake, oxidation, and oxidative phosphorylation in fat of diabetic patients and thus may have corrected, at least partially, a recently recognized defect in patients with type 2 diabetes consisting of reduced expression of genes related to oxidative metabolism and mitochondrial function.