Identification of a Physiologically Relevant Endogenous Ligand for PPARα in Liver

Chakravarthy, Manu V.; Lodhi, Irfan J.; Li, Yin; Malapaka, Raghu R.V.; Xu, H. Eric; Turk, John; Semenkovich, Clay F.

doi:10.1016/j.cell.2009.05.036

Cited by 471 publications

(440 citation statements)

References 47 publications

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“…Available ligand alters co-activator/co-repressor dynamics to induce transcription of downstream target genes. Fatty acids are a preferred PPAR␣ ligand with a wide array of other lipids also implicated in PPAR activation (15,16). PPAR␣ is expressed at high levels in liver, where its activation promotes fatty acid oxidation, ketogenesis, lipid transport, and gluconeogenesis (17).…”

Section: Discussionmentioning

confidence: 99%

Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Adams

Astapova

Fisher

et al. 2010

Journal of Biological Chemistry

119

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Thyroid hormone has profound and diverse effects on liver metabolism. Here we show that tri-iodothyronine (T3) treatment in mice acutely and specifically induces hepatic expression of the metabolic regulator fibroblast growth factor 21 (FGF21). Mice treated with T3 showed a dose-dependent increase in hepatic FGF21 expression with significant induction at doses as low as 100 g/kg. Time course studies determined that induction is seen as early as 4 h after treatment with a further increase in expression at 6 h after injection. As FGF21 expression is downstream of the nuclear receptor peroxisome proliferatoractivated receptor ␣ (PPAR␣), we treated PPAR␣ knock-out mice with T3 and found no increase in expression, indicating that hepatic regulation of FGF21 by T3 in liver is via a PPAR␣-dependent mechanism. In contrast, in white adipose tissue, FGF21 expression was suppressed by T3 treatment, with other T3 targets unaffected. In cell culture studies with an FGF21 reporter construct, we determined that three transcription factors are required for induction of FGF21 expression: thyroid hormone receptor ␤ (TR␤), retinoid X receptor (RXR), and PPAR␣. These findings indicate a novel regulatory pathway whereby T3 positively regulates hepatic FGF21 expression, presenting a novel therapeutic target for diseases such as non-alcoholic fatty liver disease.The biochemical pathways mediating the metabolism of carbohydrates, lipids, and proteins are all regulated to some degree by thyroid hormone and the thyroid hormone receptors (␣ and ␤) (1, 2), which belong to the nuclear hormone receptor superfamily (1). In the liver, the ␤ isoform of the thyroid hormone receptor (TR␤) is responsible for mediating the majority of the actions of tri-iodothyronine (T3), 2 whereas in other tissues such as the heart and brown adipose tissue, the ␣ isoform (TR␣) is the main mediator of thyroid hormone effects (3, 4). FGF21 is a member of the endocrine FGF subfamily, which also includes FGF19 and FGF23, all of which circulate and have hormone-like actions (5, 6). FGF21 is known to stimulate glucose uptake in mouse 3T3-L1 adipocytes and in primary cultures of human adipocytes and can improve glucose homeostasis when administered to obese mice (6) and non-human primates (7). Transgenic mice overexpressing FGF21 in liver display improved insulin sensitivity and glucose clearance, reduced plasma triglyceride concentrations, and are resistant to weight gain when fed a high fat diet (6).Subsequent studies showed that administration of FGF21 to mice with high fat diet-induced obesity led to increased fat utilization and energy expenditure and reduced plasma glucose, insulin, serum lipid concentrations, and hepatic triglyceride concentrations (6,8). In one study, it was shown that the decrease in hepatic triglyceride concentrations was accompanied by a decrease in lipogenic gene expression (8).FGF21 expression is known to be downstream of the nuclear receptor PPAR␣, which itself plays a significant role in lipid oxidation. FGF21 is physiologically induced u...

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Section: Discussionmentioning

confidence: 99%

Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Adams

Astapova

Fisher

et al. 2010

Journal of Biological Chemistry

119

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“…Both in farmed and wild tuna, PC 16:0/18:1 was detected intensely. PC 16:0/18:1 is reported to be a physiologically relevant endogenous peroxisome proliferator-activated receptor PPAR α ligand 6 . PPARα regulates the expression of enzymes related to the β-oxidation of fatty acids.…”

Section: Lipid Profi Les Of Farmed and Wild Bluefi N Tunamentioning

confidence: 99%

Selective Analysis of Lipids by Thin-Layer Chromatography Blot Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry

et al. 2011

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“…Newly synthesized FAs also serve as signaling molecules and modulators of transcription factor activity (1)(2)(3). Excess accumulation of FAs in tissues contributes to the pathogenesis of many common diseases, including insulin resistance, nonalcoholic fatty liver disease, diabetes, and cancer (4,5).…”

mentioning

confidence: 99%

Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis

Kim

Moon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

120

137

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Acetyl-CoA carboxylase (ACC), the first committed enzyme in fatty acid (FA) synthesis, is regulated by phosphorylation/dephosphorylation, transcription, and an unusual mechanism of protein polymerization. Polymerization of ACC increases enzymatic activity and is induced in vitro by supraphysiological concentrations of citrate (>5 mM). Here, we show that MIG12, a 22 kDa cytosolic protein of previously unknown function, binds to ACC and lowers the threshold for citrate activation into the physiological range (<1 mM). In vitro, recombinant MIG12 induced polymerization of ACC (as determined by nondenaturing gels, FPLC, and electron microscopy) and increased ACC activity by >50-fold in the presence of 1 mM citrate. In vivo, overexpression of MIG12 in liver induced ACC polymerization, increased FA synthesis, and produced triglyceride accumulation and fatty liver. Thus, in addition to its regulation by phosphorylation and transcription, ACC is regulated at a tertiary level by MIG12, which facilitates ACC polymerization and enhances enzymatic activity.lipogenesis | SREBPs | steatosis F atty acids (FAs) are the essential components of phospholipids and provide the most important energy depot for the body in the form of triglycerides (TG). Newly synthesized FAs also serve as signaling molecules and modulators of transcription factor activity (1-3). Excess accumulation of FAs in tissues contributes to the pathogenesis of many common diseases, including insulin resistance, nonalcoholic fatty liver disease, diabetes, and cancer (4, 5). Given the central role of FAs in these diseases, the enzymes of FA biosynthesis are potential therapeutic targets.The first committed step in FA biosynthesis is carried out by acetyl-CoA carboxylase (ACC). ACC1 was isolated and characterized by Wakil et al. (6) and functions to carboxylate acetyl-CoA to form malonyl-CoA. Subsequently, a second ACC isoform, ACC2, was identified in mammals that is encoded by a separate gene but carries out the same enzymatic reaction (7,8).ACCs are members of a larger family of carboxylases that require biotin and ATP and use bicarbonate as a carbon donor. The malonyl-CoA produced by ACC can be used by FA synthase (FAS) for the sequential 2-carbon elongation reactions that generate palmitic acid (C16:0) in the cytosol. While both ACC1 and ACC2 produce malonyl-CoA, ACC1 is predominantly cytosolic and generates malonyl-CoA that is used by FAS to synthesize palmitic acid. ACC2 is associated with the mitochondrial membrane (9) and produces malonyl-CoA that serves to allosterically inhibit carnitine palmitoyl transferase I, the protein responsible for transport of long chain FAs into mitochondria for β-oxidation (10).Regulation of ACC1 and ACC2 occurs at multiple levels. ACC activity is acutely regulated by phosphorylation/dephosphorylation. AMP-activated protein kinase phosphorylates ACC and inhibits enzyme activity (11). In the fed state, excess glucose must be converted to FAs for energy storage in the form of TGs. Increased insulin signaling in the fed state res...

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Identification of a Physiologically Relevant Endogenous Ligand for PPARα in Liver

Cited by 471 publications

References 47 publications

Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Selective Analysis of Lipids by Thin-Layer Chromatography Blot Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry

Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis

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