PPARδ activation attenuates hepatic steatosis in Ldlr mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity

PPARδ regulates systemic lipid homeostasis and inflammation, but its role in hepatic lipid metabolism remains unclear. Here, we examine whether intervening with a selective PPARδ agonist corrects hepatic steatosis induced by a high-fat, cholesterol-containing (HFHC) diet. Ldlr−/− mice were fed a chow or HFHC diet (42% fat, 0.2% cholesterol) for 4 weeks. For an additional 8 weeks, the HFHC group was fed HFHC or HFHC plus GW1516 (3 mg/kg/day). GW1516-intervention significantly attenuated liver TG accumulation by induction of FA β-oxidation and attenuation of FA synthesis. In primary mouse hepatocytes, GW1516 treatment stimulated AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation in WT hepatocytes, but not AMPKβ1−/− hepatocytes. However, FA oxidation was only partially reduced in AMPKβ1−/− hepatocytes, suggesting an AMPK-independent contribution to the GW1516 effect. Similarly, PPARδ-mediated attenuation of FA synthesis was partially due to AMPK activation, as GW1516 reduced lipogenesis in WT hepatocytes but not AMPKβ1−/− hepatocytes. HFHC-fed animals were hyperinsulinemic and exhibited selective hepatic insulin resistance, which contributed to elevated fasting FA synthesis and hyperglycemia. GW1516 intervention normalized fasting hyperinsulinemia and selective hepatic insulin resistance and attenuated fasting FA synthesis and hyperglycemia. The HFHC diet polarized the liver toward a proinflammatory M1 state, which was reversed by GW1516 intervention. Thus, PPARδ agonist treatment inhibits the progression of preestablished hepatic steatosis. PPARδ regulates systemic lipid homeostasis and inflammation, but its role in hepatic lipid metabolism remains unclear. Here, we examine whether intervening with a selective PPARδ agonist corrects hepatic steatosis induced by a high-fat, cholesterol-containing (HFHC) diet. Ldlr−/− mice were fed a chow or HFHC diet (42% fat, 0.2% cholesterol) for 4 weeks. For an additional 8 weeks, the HFHC group was fed HFHC or HFHC plus GW1516 (3 mg/kg/day). GW1516-intervention significantly attenuated liver TG accumulation by induction of FA β-oxidation and attenuation of FA synthesis. In primary mouse hepatocytes, GW1516 treatment stimulated AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation in WT hepatocytes, but not AMPKβ1−/− hepatocytes. However, FA oxidation was only partially reduced in AMPKβ1−/− hepatocytes, suggesting an AMPK-independent contribution to the GW1516 effect. Similarly, PPARδ-mediated attenuation of FA synthesis was partially due to AMPK activation, as GW1516 reduced lipogenesis in WT hepatocytes but not AMPKβ1−/− hepatocytes. HFHC-fed animals were hyperinsulinemic and exhibited selective hepatic insulin resistance, which contributed to elevated fasting FA synthesis and hyperglycemia. GW1516 intervention normalized fasting hyperinsulinemia and selective hepatic insulin resistance and attenuated fasting FA synthesis and hyperglycemia. The HFHC diet polarized the liver toward a proinflammatory M1 state, which was reversed by GW1516 intervention. Thus, PPARδ agonist treatment inhibits the progression of preestablished hepatic steatosis. Hepatic steatosis, defined as excessive lipid accumulation in the liver, is observed in >40% of patients with type 2 diabetes (1Farese Jr, R.V. Zechner R. Newgard C.B. Walther T.C. The problem of establishing relationships between hepatic steatosis and hepatic insulin resistance.Cell Metab. 2012; 15: 570-573Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 2Williamson R.M. Price J.F. Glancy S. Perry E. Nee L.D. Hayes P.C. Frier B.M. Van Look L.A. Johnston G.I. Reynolds R.M. et al.Prevalence of and risk factors for hepatic steatosis and nonalcoholic Fatty liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study.Diabetes Care. 2011; 34: 1139-1144Crossref PubMed Scopus (288) Google Scholar). Although a causal relationship between hepatic steatosis and insulin resistance has been difficult to define (1Farese Jr, R.V. Zechner R. Newgard C.B. Walther T.C. The problem of establishing relationships between hepatic steatosis and hepatic insulin resistance.Cell Metab. 2012; 15: 570-573Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar), inflammation has been implicated as a contributing factor to dysregulated hepatic insulin signaling (3Hummasti S. Hotamisligil G.S. Endoplasmic reticulum stress and inflammation in obesity and diabetes.Circ. Res. 2010; 107: 579-591Crossref PubMed Scopus (328) Google Scholar). As a consequence, hyperinsulinemia-mediated lipogenesis ensues, which along with suppressed FA oxidation contributes to ectopic lipid deposition (4Brown M.S. Goldstein J.L. Selective versus total insulin resistance: a pathogenic paradox.Cell Metab. 2008; 7: 95-96Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar). Prolonged hepatic steatosis can result in nonalcoholic steatohepatitis, cirrhosis, and eventually liver failure (3Hummasti S. Hotamisligil G.S. Endoplasmic reticulum stress and inflammation in obesity and diabetes.Circ. Res. 2010; 107: 579-591Crossref PubMed Scopus (328) Google Scholar). However, few therapeutic strategies exist that effectively correct hepatic steatosis in the setting of insulin resistance. At a molecular level, insulin binding to its cognate receptor leads to receptor-mediated tyrosine phosphorylation of insulin receptor substrates (IRS-1 and/or IRS-2), which in turn activate phosphoinositide 3-kinase (PI3-K) to simulate the phosphorylation and of protein kinase the insulin receptor and its Metab. Google Scholar). in the of hepatic due to phosphorylation and of and the of lipogenesis due to phosphorylation and of the of S. M.S. Goldstein J.L. of insulin signaling in for of but not of 2010; 107: PubMed Scopus Google Scholar). However, in the liver, its to but its to activate S. M.S. Goldstein J.L. of insulin signaling in for of but not of 2010; 107: PubMed Scopus Google Scholar). of the of binding protein remains S. M.S. Goldstein J.L. of insulin signaling in for of but not of 2010; 107: PubMed Scopus Google Scholar). In insulin the of that J.L. S. S. Hotamisligil G.S. et hepatic and lipogenesis and Metab. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar). 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As we L.A. et receptor agonist GW1516 inflammation, insulin resistance, and in receptor 34: PubMed Scopus Google Scholar), the HFHC diet in progression of fasting hyperinsulinemia the hyperinsulinemia was attenuated by intervention with GW1516 to the HFHC diet Selective hepatic insulin resistance was a fasting with phosphorylation of hepatic was significantly elevated in the in HFHC-fed and the to was for was observed in However, in HFHC-fed the phosphorylation of was elevated in the state, and the to was In GW1516 intervention the of to observed in is with in the of the insulin signaling in HFHC-fed mice (4Brown M.S. Goldstein J.L. 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GW1516 intervention normalized the in the of the was not by the HFHC was by GW1516 that the HFHC diet the was to the PPARδ attenuated the HFHC of the The of which for was by GW1516 in primary hepatocytes not suggesting that the in in was to hepatic steatosis. the of the PPARδ agonist GW1516 to the progression of hepatic steatosis. GW1516 intervention the progression of liver TG the of reduced FA synthesis and FA GW1516 hepatic AMPK in and in of hepatocytes in AMPK to GW1516 that of lipogenesis the induction of FA oxidation was of by AMPK Hepatic lipogenesis was attenuated of selective hepatic insulin resistance, which was with reduced hepatic inflammation The role of PPARδ in liver TG metabolism has been et regulates metabolism and insulin PubMed Scopus Google Scholar, S. of and of in mice fed a and PubMed Scopus Google Scholar, and hepatic lipogenesis in 2008; PubMed Scopus Google Scholar, E. R. 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The with and that intervention to an HFHC diet with GW1516 in mice progression of hepatic steatosis and corrects selective hepatic insulin resistance by signaling in of only was but of to its was The of contributes to and hepatic lipogenesis in 2008; PubMed Scopus Google Scholar). factors to were or were not and J.L. S. S. Hotamisligil G.S. et hepatic and lipogenesis and Metab. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar, and hepatic lipogenesis in 2008; PubMed Scopus Google Scholar, E. et regulates to the 2011; Full Text Full Text PDF PubMed Scopus Google Scholar). the of the contributed to the of in FA synthesis. GW1516 reduced lipogenesis in WT primary mouse hepatocytes, but not in hepatocytes, that of FA synthesis was AMPK Although to the observed in lipogenesis by GW1516 the of to the in insulin in which insulin and the insulin contributes to hepatic steatosis, and (4Brown M.S. Goldstein J.L. Selective versus total insulin resistance: a pathogenic paradox.Cell Metab. 2008; 7: 95-96Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar). In the we that hepatic insulin signaling in in a of insulin resistance. we that PPARδ the progression of the selective hepatic as of and was in the GW1516-intervention the of that PPARδ not only insulin resistance et regulates metabolism and insulin PubMed Scopus Google Scholar, S. et of receptor in and PubMed Scopus Google Scholar, S. R.M. receptor metabolism to Full Text Full Text PDF PubMed Scopus Google Scholar), but can preestablished hepatic insulin resistance. inflammation has been to hepatic steatosis and insulin resistance (3Hummasti S. Hotamisligil G.S. Endoplasmic reticulum stress and inflammation in obesity and diabetes.Circ. Res. 2010; 107: 579-591Crossref PubMed Scopus (328) Google Scholar, Hotamisligil G.S. in 2011; PubMed Scopus Google Scholar). inflammation in by lipid accumulation and insulin resistance S. The the of insulin resistance and Res. PubMed Scopus Google Scholar, The of insulin resistance Res. 2010; PubMed Scopus Google Scholar). the selective and TG in of HFHC-fed animals and by GW1516 is to that induction and attenuation of and hepatic of in mice in proinflammatory and reduced which was to liver TG accumulation and hepatic of by insulin resistance.Cell Metab. 2008; 7: Full Text Full Text PDF PubMed Scopus Google Scholar). with an role for PPARδ in the liver, to the in and in the et regulates proinflammatory to 2008; PubMed Scopus Google Scholar, L.A. et receptor agonist GW1516 inflammation, insulin resistance, and in receptor 34: PubMed Scopus Google Scholar, L.A. of receptor inhibits and the induced by 2012; PubMed Scopus Google Scholar). 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