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Previous studies have shown that administration of fibroblast growth factor-19 (FGF-19) reverses diabetes, hepatic steatosis, hyperlipidemia, and adipose accretion in animal models of obesity. To investigate the mechanism for this effect, we determined whether FGF-19 modulated hepatic fatty acid synthesis, a key process controlling glucose tolerance and triacylglycerol accumulation in liver, blood, and adipose tissue. Metabolic syndrome is a state of metabolic dysregulation that is characterized by obesity, hepatic steatosis, hyperlipidemia, atherosclerosis, and glucose intolerance (1). A key mechanism contributing to the development of metabolic syndrome is an elevation in the rate of hepatic fatty acid synthesis (2, 3). Hepatic fatty acid synthesis drives the synthesis of triacylglycerols that accumulate in the liver, blood, and adipose tissue. An elevation in hepatic fatty acid synthesis also promotes glucose intolerance, as accumulation of fatty acid metabolites in the liver suppresses the ability of insulin activate glycogen synthesis and inhibit gluconeogenesis (3). Accordingly, one approach to treating metabolic syndrome has been to manipulate the activity of signal transduction pathways that modulate hepatic fatty acid synthesis. For example, the beneficial effect of metformin on glucose tolerance in diabetic animals is mediated by a decrease in the rate of hepatic fatty acid synthesis (4). Metformin suppresses fatty acid synthesis by inhibiting the activity of acetyl-CoA carboxylase-␣ (ACC␣) 2 and decreasing the expression of sterol regulatory element-binding protein-1c (SREBP-1c), a key transcriptional activator of lipogenic genes. Metformin also increases the rate of hepatic fatty acid oxidation, an effect that contributes to the improvement in glucose tolerance. Metformin-induced changes in hepatic fatty acid synthesis and fatty acid oxidation are mediated by an activation of AMP-activated protein kinase (AMPK). As metformin administration causes undesirable side effects, the identification of new signaling pathways that modulate hepatic fatty acid metabolism may lead to the development of more effective therapies for treating metabolic syndrome.Fibroblast growth factor-19 (FGF-19) was originally identified as a signal promoting the development of the inner ear in chick embryos (5). Subsequent studies have shown that FGF-19 and its mouse ortholog, FGF-15, also function in adult animals. For example, FGF-19/FGF-15 expressed in the small intestine acts as an enterohepatic hormone, mediating the inhibitory effects of intestinal bile acids on expression of hepatic cholesterol 7␣-hydroxylase (CYP7A1), a key regulatory step in the bile acid synthesis pathway (6, 7). FGF-19 also regulates carbohydrate and lipid metabolism in adult animals. Administration of recombinant human FGF-19 or transgenic expression of the human FGF-19 gene in obese/diabetic mice causes an increase in energy expenditure and a decrease in adipose tissue stores (8, 9). Treatment of obese/diabetic mice with FGF-19 also reduces serum and...

Background:The hormone FGF21 is a potent regulator of carbohydrate and lipid metabolism and a promising drug for treating metabolic syndrome. Results: Farnesoid X receptor (FXR) agonists and FGF19 induce hepatic FGF21 secretion via a transcriptional mechanism and posttranscriptional mechanism, respectively. Conclusion: Activation of the FXR pathway stimulates FGF21 expression and secretion. Significance: Activation of FXR is a potential approach to enhance endogenous FGF21 production and reverse metabolic syndrome.

In previous work, we characterized a 3,5,3-triiodothyronine response element (T3RE) in acetyl-CoA carboxylase-␣ (ACC␣) promoter 2 that mediated 3,5,3-triiodothyronine (T3) regulation of ACC␣ transcription in chick embryo hepatocytes. Sequence comparison analysis revealed the presence of sterol regulatory element-1 (SRE-1) located 5 bp downstream of the ACC␣ T3RE. Here, we investigated the role of this SRE-1 in modulating T3 regulation of ACC␣ transcription. Transfection analyses demonstrated that the SRE-1 enhanced T3-induced ACC␣ transcription by more than 2-fold in hepatocytes. The effect of the SRE-1 on T3 responsiveness required the presence of the T3RE in its native orientation. In pull-down experiments, the mature form of sterol regulatory element-binding protein-1 (SREBP-1) specifically bound the ␣-isoform of the nuclear T3 receptor (TR), and the presence of T3 enhanced this interaction. A region of TR␣ containing the DNA-binding domain plus flanking sequences (amino acids 21-157) was required for interaction with SREBP-1, and a region of SREBP-1 containing the basic helix-loop-helix-leucine zipper domain (amino acids 300 -389) was required for interaction with TR␣. In gel mobility shift experiments, TR␣, retinoid X receptor-␣, and mature SREBP-1 formed a tetrameric complex on a DNA probe containing the ACC␣ T3RE and SRE-1, and the presence of T3 enhanced the formation of this complex. Formation of the tetrameric complex stabilized the binding of SREBP-1 to the SRE-1. These results indicate that SREBP-1 directly interacts with TR-retinoid X receptor in an orientationspecific manner to enhance T3-induced ACC␣ transcription in hepatocytes. T3 regulation of ACC␣ transcription in nonhepatic cell cultures such as chick embryo fibroblasts is markedly reduced compared with that of chick embryo hepatocytes. Here, we also show that alterations in SREBP expression play a role in mediating cell typedependent differences in T3 regulation of ACC␣ transcription.

In birds and mammals, agonists of the liver X receptor (LXR) increase the expression of enzymes that make up the fatty acid synthesis pathway. Here, we investigate the mechanism by which the synthetic LXR agonist, T0-901317, increases the transcription of the acetyl-coenzyme A carboxylase-a (ACCa) gene in chick embryo hepatocyte cultures. Transfection analyses demonstrate that activation of ACCa transcription by T0-901317 is mediated by a cis-acting regulatory unit (2101 to 271 bp) that is composed of a liver X receptor response element (LXRE) and a sterol-regulatory element (SRE). The SRE enhances the ability of the LXRE to activate ACCa transcription in the presence of T0-901317. Treating hepatocytes with T0-901317 increases the concentration of mature sterol-regulatory element binding protein-1 (SREBP-1) in the nucleus and the acetylation of histone H3 and histone H4 at the ACCa LXR response unit. These results indicate that T0-901317 increases hepatic ACCa transcription by directly activating LXR&retinoid X receptor (RXR) heterodimers and by increasing the activity of an accessory transcription factor (SREBP-1) that enhances ligand induced-LXR&RXR activity.-Talukdar, S., and F. B. Hillgartner. The mechanism mediating the activation of acetyl-coenzyme A carboxylase-a gene transcription by the liver X receptor agonist T0-901317. J. Lipid Res. 2006Res. . 47: 2451Res. -2461