Human liver PPARα gene expression negatively correlates with NASH severity, visceral adiposity and insulin resistance and positively with adiponectin. Histological improvement is associated with an increase in expression of PPARα and its target genes. These data might suggest that PPARα is a potential therapeutic target in NASH.

Abstract-Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase used in the prevention of cardiovascular disease (CVD). In addition to their cholesterol-lowering activities, statins exert pleiotropic antiinflammatory effects, which might contribute to their beneficial effects not only on CVD but also on lipid-unrelated immune and inflammatory diseases, such as rheumatoid arthritis, asthma, stroke, and transplant rejection. However, the molecular mechanisms involved in these antiinflammatory properties of statins are unresolved. Here we show that the peroxisome proliferator-activated receptor (PPAR) ␣ mediates antiinflammatory effects of simvastatin in vivo in models of acute inflammation. The inhibitory effects of statins on lipopolysaccharide-induced inflammatory response genes were abolished in PPAR␣-deficient macrophages and neutrophils. Moreover, simvastatin inhibited PPAR␣ phosphorylation by lipopolysaccharide-activated protein kinase C (PKC) ␣. A constitutive active form of PKC␣ inhibited nuclear factor B transrepression by PPAR␣ whereas simvastatin enhanced transrepression activity of wild-type PPAR␣, but not of PPAR␣ mutated in its PKC phosphorylation sites. These data indicate that the acute antiinflammatory effect of simvastatin occurs via PPAR␣ by a mechanism involving inhibition of PKC␣ inactivation of PPAR␣ transrepression activity. Key Words: inflammation Ⅲ macrophages Ⅲ neutrophils Ⅲ nuclear receptors Ⅲ statins Ⅲ PKC S tatins, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the ratelimiting enzyme in cholesterol synthesis, are widely prescribed for the treatment of hypercholesterolemia. 1 In addition to plasma lipid-modulating action, statins exert pleiotropic antiinflammatory effects, which might contribute to their beneficial effects on cardiovascular disease (CVD). 2 Emerging evidences also suggest beneficial therapeutic activities of statins in immune and inflammatory diseases such as multiple sclerosis, Alzheimer's disease, ischemic stroke, transplant rejection, rheumatoid arthritis, and asthma. [3][4][5][6] Several clinical observations indicate that these effects cannot be attributed to their cholesterol-lowering activities only. 7 Statin therapy decreases plasma concentrations of inflammatory markers, such as C-reactive protein (CRP), within 1 week after treatment initiation, before any lipid changes are observed. 8 Statin treatment reduces the incidence of ischemic stroke for which plasma cholesterol levels are not considered a risk factor. 9 Moreover, statins also exert antiinflammatory actions in animal models, which are resistant to their hypolipidemic actions. 10 In models of acute and chronic inflammation, statins inhibit endothelial adhesion and transendothelial migration of leukocytes to sites of inflammation, 10 acting both on endothelial cells and leukocytes. Statins modulate macrophage functions by inhibiting the activation of inflammatory response genes, such as interleukin (IL)-1b and IL-6, tumor necrosis...