PPAR control: it's SIRTainly as easy as PGC

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   Figure 1

   Overview of PGC-1α post-translational modification. Post-translational modification of PGC-1α by reversible acetylation, phosphorylation, and methylation are key regulatory factors for PGC-1α function. SIRT1-mediated deacetylation activates PGC-1α, while acetylation by GCN5 inhibits PGC-1α-directed gene expression. In skeletal muscle, phosphorylation by AMPK and p38 MAPK increases stabilization of PGC-1α. In contrast, AKT/PKB-mediated phosphorylation facilitates degradation of hepatic PGC-1α. PRMT1 also activates PGC-1α through methylation at several arginine residues. Ac, acetyl group; AMPK, AMP-dependent protein kinase; HAT, histone acetyl transferase; HDAC, histone deacetylase; MAPK, mitogen-activated protein kinase; Me, methyl group; NR, nuclear receptor; P, phosphate group; PGC-1α, peroxisome proliferator- activated receptor γ coactivator 1α; PPARα, peroxisome proliferator-activated receptor α; PPRE, PPAR response element; PRMT1, protein arginine methyltransferase 1; RXR, retinoid X receptor; SIRT1, sirtuin 2 ortholog 1.
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   Figure 2

   The critical role of PGC-1α in the regulation of hepatic gluconeogenesis. Glucagon stimulates the dephosphorylation and translocation of the CREB-regulated transcriptional coactivator (TORC2) to the nucleus, where it coactivates CREB leading to induction of PGC-1α. PGC-1α subsequently coactivates and forms complexes with FoxO1, the GR and HNF-4α (as well as PPARα) and induction of gluconeogenic gene expression. Activation of Akt by insulin phosphorylates TORC2 and PGC-1α leading to their degradation. PGC-1α is deacetylated by SIRT1, induction of PGC-1α being associated with coactivation of FoxO1 and HNF-4α and induction of gluconeogenic gene expression. This PGC-1α-directed gluconeogenic gene expression pathway is inhibited by GCN5. Ac, acetyl group; CREB, cAMP response element-binding protein; FoxO1, forkhead box O1; GR, glucocorticoid receptor; HNF-4α, hepatocyte nuclear factor-4α; P, phosphate group; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1α; PPARα, peroxisome proliferator-activated receptor α; SIRT1, sirtuin 2 ortholog 1; TORC2, CREB-regulated transcriptional coactivator 2.
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   Figure 3

   Overview of lipin-1 regulation of PGC1α–PPARα-directed gene expression. Lipin-1 is reported to enhance PPARα–PGC-1α-directed gene expression through induction of PPARα transcription and by forming a complex with PGC-1α and PPARα, leading to increased FA oxidation. In contrast, TORC2-mediated induction of lipin-1 leads to increased DAG and TAG synthesis. Ac, acetyl group; AMPK, AMP-dependent protein kinase; DAG, diacylglycerol; FAO, fatty acid oxidation; HAT, histone acetyl transferase; LXR, liver X receptor; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1 α; PKC, protein kinase C; PPARα, peroxisome proliferator-activated receptor α; PPRE, PPAR response element; RXR, retinoid X receptor; SIRT1, sirtuin 2 ortholog 1; SREBP-1, sterol regulatory element binding protein 1; TAG, triacylglycerol; TORC2, CREB-regulated transcriptional coactivator 2.
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   Figure 4

   The critical role of PGC-1β in stimulating hepatic lipid synthesis and secretion. PGC-1β is induced in liver in response to high dietary saturated fat and fructose. PGC-1β coactivates SREBP-1c and increases the expression of a range of genes involved in the synthesis of FA, TAG and cholesterol, including FAS, SCD-1, HMG-CoA reductase, DGAT and GPAT. PGC-1β also stimulates VLDL secretion, possibly via augmenting activation of LXRα, leading to hypertriglyceridemia and accumulation of cholesterol in VLDL, the precursor to LDL cholesterol. LXR, liver X receptor; PGC-1β, peroxisome proliferator-activated receptor γ coactivator 1β; RXR, retinoid X receptor; SREBP, sterol regulatory element-binding protein; VLDL, very low-density lipoprotein; ?, indicates potential mechanism.

• © 2010 Society for Endocrinology