The farnesoid X receptor (FXR) is a bile acid (BA)-activated nuclear receptor that plays a major role in the regulation of BA and lipid metabolism. Recently, several studies have suggested a potential role of FXR in the control of hepatic carbohydrate metabolism, but its contribution to the maintenance of peripheral glucose homeostasis remains to be established. FXR-deficient mice display decreased adipose tissue mass, lower serum leptin concentrations, and elevated plasma free fatty acid levels. Glucose and insulin tolerance tests revealed that FXR deficiency is associated with impaired glucose tolerance and insulin resistance. Moreover, whole-body glucose disposal during a hyperinsulinemic euglycemic clamp is decreased in FXR-deficient mice. In parallel, FXR deficiency alters distal insulin signaling, as reflected by decreased insulin-dependent Akt phosphorylation in both white adipose tissue and skeletal muscle. Whereas FXR is not expressed in skeletal muscle, it was detected at a low level in white adipose tissue in vivo and induced during adipocyte differentiation in vitro. Moreover, mouse embryonic fibroblasts derived from FXR-deficient mice displayed impaired adipocyte differentiation, identifying a direct role for FXR in adipocyte function. Treatment of differentiated 3T3-L1 adipocytes with the FXR-specific synthetic agonist GW4064 enhanced insulin signaling and insulin-stimulated glucose uptake. Finally, treatment with GW4064 improved insulin resistance in genetically obese ob/ob mice in vivo. Although the underlying molecular mechanisms remain to be unraveled, these results clearly identify a novel role of FXR in the regulation of peripheral insulin sensitivity and adipocyte function. This unexpected function of FXR opens new perspectives for the treatment of type 2 diabetes.The farnesoid X receptor (FXR) 4 (NR1H4) is a nuclear receptor that is activated by bile acids (BAs) (1). A major physiological role of FXR is to protect liver cells from the deleterious effect of BA overload by decreasing their endogenous production and by accelerating BA biotransformation and excretion (1). In addition, the generation and characterization of FXR-deficient (FXR Ϫ/Ϫ ) mice has also established a critical role of FXR in lipid metabolism, since these mice display elevated serum levels of triglycerides and high density lipoprotein cholesterol (2). Recently, several studies have suggested that FXR might also regulate hepatic carbohydrate metabolism (3). The first indication came from the observation that hepatic FXR expression is reduced in several rodent models of diabetes (4). FXR expression also varies in mouse liver during nutritional changes, being increased during fasting and decreased upon refeeding (5, 6). Moreover, FXR activation by BAs or the synthetic nonsteroidal specific agonist GW4064 (7) modulates the expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (3). However, conflicting data report either a positive (8) or a negative effect (9, 10) of BA and/or GW4064 on phosphoenolpyruvate...

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The liver plays a central role in the control of blood glucose homeostasis by maintaining a balance between glucose production and utilization. The farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor. Hepatic FXR expression is regulated by glucose and insulin. Here we identify a role for FXR in the control of hepatic carbohydrate metabolism. When submitted to a controlled fasting-refeeding schedule, FXR ؊/؊ mice displayed an accelerated response to high carbohydrate refeeding with an accelerated induction of glycolytic and lipogenic genes and a more pronounced repression of gluconeogenic genes. Plasma insulin and glucose levels were lower in FXR ؊/؊ mice upon refeeding the highcarbohydrate diet. These alterations were paralleled by decreased hepatic glycogen content. Hepatic insulin sensitivity was unchanged in FXR ؊/؊ mice. Treatment of isolated primary hepatocytes with a synthetic FXR agonist attenuated glucose-induced mRNA expression as well as promoter activity of L-type pyruvate kinase, acetyl-CoA carboxylase 1, and Spot14. Moreover, activated FXR interfered negatively with the carbohydrate response elements regions. These results identify a novel role for FXR as a modulator of hepatic carbohydrate metabolism.The liver plays a major role in maintaining plasma glucose homeostasis by controlling a delicate balance between hepatic glucose uptake/utilization and hepatic glucose production. In the fed state, the liver stores energy from glucose by synthesizing glycogen and fat. Conversely, when plasma glucose concentrations decrease during fasting, the liver produces glucose by the glycogenolytic and gluconeogenic pathways. This fasting-refeeding transition involves a highly coordinated adaptation of the expression of genes encoding key metabolic enzymes that is orchestrated by hormones and nutrients.In the fed state, insulin and glucose act in concert to promote

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Objective-Hypertriglyceridemia and fatty liver are common in patients with type 2 diabetes, but the factors connecting alterations in glucose metabolism with plasma and liver lipid metabolism remain unclear. Apolipoprotein CIII (apoCIII), a regulator of hepatic and plasma triglyceride metabolism, is elevated in type 2 diabetes. In this study, we analyzed whether apoCIII is affected by altered glucose metabolism. Methods and Results-Liver-specific insulin receptor-deficient mice display lower hepatic apoCIII mRNA levels than controls, suggesting that factors other than insulin regulate apoCIII in vivo. Glucose induces apoCIII transcription in primary rat hepatocytes and immortalized human hepatocytes via a mechanism involving the transcription factors carbohydrate response element-binding protein and hepatocyte nuclear factor-4␣. ApoCIII induction by glucose is blunted by treatment with agonists of farnesoid X receptor and peroxisome proliferator-activated receptor-␣ but not liver X receptor, ie, nuclear receptors controlling triglyceride metabolism. Moreover, in obese humans, plasma apoCIII protein correlates more closely with plasma fasting glucose and glucose excursion after oral glucose load than with insulin. Conclusion-Glucose induces apoCIII transcription, which may represent a mechanism linking hyperglycemia, hypertriglyceridemia, and cardiovascular disease in type 2 diabetes. Key Words: apolipoproteins Ⅲ lipids Ⅲ metabolism Ⅲ nuclear receptors Ⅲ type II diabetes T ype 2 diabetes is a progressive disease that is due to increased insulin resistance and progressive pancreatic failure. Type 2 diabetic patients often display lipid metabolism abnormalities (namely hypertriglyceridemia; low highdensity lipoprotein-cholesterol levels; and increased small, dense low-density lipoprotein particles) that result in increased cardiovascular disease risk. Epidemiological studies identified hypertriglyceridemia as an independent risk factor for atherosclerosis. 1 The hypertriglyceridemia is due to hepatic overproduction of triglyceride-rich very-low-density lipoprotein particles, 2 as well as impaired intravascular catabolism as a result of decreased lipoprotein lipase activity. 2 See accompanying article on page 471Apolipoprotein CIII (apoCIII) is a 79-amino-acid glycoprotein synthesized in the liver and the intestine 3 that controls triglyceride metabolism in humans 4 and mice. 5 ApoCIII is a component of triglyceride-rich lipoproteins, low-density lipoprotein, and high-density lipoprotein. 6 Plasma triglyceride and apoCIII concentrations positively correlate in normo-and hypertriglyceridemic subjects. 7-10 ApoCIII gene deficiency results in a hypotriglyceridemia because of an accelerated catabolism of triglyceride rich-lipoproteins, 4,5 whereas apo-CIII overexpression in mice leads to hypertriglyceridemia. 11 In vitro and in vivo studies have established that apoCIII delays the catabolism of triglyceride-rich lipoproteins by inhibiting lipoprotein lipase 12,13 and inhibits the hepatic uptake of triglyceride-rich rem...

Glucuronidation, a major metabolic pathway for a large variety of endobiotics and xenobiotics, is catalyzed by enzymes belonging to the UDP-glucuronosyltransferase (UGT) family. Among UGT enzymes, UGT2B4 conjugates a large variety of endogenous and exogenous molecules and is considered to be the major bile acid conjugating UGT enzyme in human liver. In the present study, we identify UGT2B4 as a novel target gene of the nuclear receptor peroxisome proliferatoractivated receptor ␣ (PPAR␣), which mediates the hypolipidemic action of fibrates. Incubation of human hepatocytes or hepatoblastoma HepG2 and Huh7 cells with synthetic PPAR␣ agonists, fenofibric acid, or Wy 14643 resulted in an increase of UGT2B4 mRNA levels. Furthermore, treatment of HepG2 cells with Wy 14643 induced the glucuronidation of hyodeoxycholic acid, a specific bile acid UGT2B4 substrate. Analysis of UGT2B mRNA and protein levels in PPAR␣ wild type and null mice revealed that PPAR␣ regulates both basal and fibrate-induced expression of these enzymes in rodents also. Finally, a PPAR response element was identified in the UGT2B4 promoter by site-directed mutagenesis and electromobility shift assays. These results demonstrate that PPAR␣ agonists may control the catabolism of cytotoxic bile acids and reinforce recent data indicating that PPAR␣, which has been largely implicated in the control of lipid and cholesterol metabolism, is also an important modulator of the metabolism of endobiotics and xenobiotics in human hepatocytes.

The apolipoprotein A5 gene (APOA5) has been repeatedly implicated in lowering plasma triglyceride levels. Since several studies have demonstrated that hyperinsulinemia is associated with hypertriglyceridemia, we sought to determine whether APOA5 is regulated by insulin. Here, we show that cell lines and mice treated with insulin down-regulate APOA5 expression in a dose-dependent manner. Furthermore, we found that insulin decreases human APOA5 promoter activity, and subsequent deletion and mutation analyses uncovered a functional E box in the promoter. Electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated that this APOA5 E box binds upstream stimulatory factors (USFs). Moreover, in transfection studies, USF1 stimulates APOA5 promoter activity, and the treatment with insulin reduced the binding of USF1/USF2 to the APOA5 promoter. The inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway abolished insulin's effect on APOA5 gene expression, while the inhibition of the P70 S6 kinase pathway with rapamycin reversed its effect and increased APOA5 gene expression. Using an oligonucleotide precipitation assay for USF from nuclear extracts, we demonstrate that phosphorylated USF1 fails to bind to the APOA5 promoter. Taken together, these data indicate that insulin-mediated APOA5 gene transrepression could involve a phosphorylation of USFs through the PI3K and P70 S6 kinase pathways that modulate their binding to the APOA5 E box and results in APOA5 down-regulation. The effect of exogenous hyperinsulinemia in men showed a decrease in the plasma ApoAV level. These results suggest a potential contribution of the APOA5 gene in hypertriglyceridemia associated with hyperinsulinemia.Several epidemiological studies have established that, in addition to an elevated cholesterol level in low-density lipoprotein and reduced cholesterol level in high-density lipoprotein (HDL), hypertriglyceridemia is an independent risk factor for coronary heart diseases (12, 22). Moreover, hypertriglyceridemia is often associated with the metabolic syndrome that characterizes diabetes and obesity (21,35). Type 2 diabetes is frequently linked to hyperglycemia, hyperinsulinemia, and hypertriglyceridemia, and the leading cause of death for individuals with diabetes is cardiovascular diseases (34).The apolipoprotein A5 gene (APOA5) was identified through comparative sequence analysis of genomic DNA sequences and has been shown to be important in determining plasma triglyceride levels in mice and humans (42). This gene is mainly expressed in the liver and resides in HDL and very low density lipoprotein particles (42,59). It has been demonstrated that mice expressing a human APOA5 transgene showed a decrease in plasma triglyceride concentration to one-third the levels in control mice. Conversely, knockout mice lacking APOA5 had four times as much plasma triglycerides as controls. Moreover, adenoviral overexpression of APOA5 reduced serum levels of triglycerides and cholesterol in mice (60). Recent works focused on th...