PPARα is robustly expressed in normal liver and stimulates expression of enzymes involved in fatty acid oxidation. The key role of PPARs in the regulation of hepatic lipid metabolism (Supporting Table 4) is further underlined by the development of hepatic steatosis in PPARα−/− mice,86,87 whereas PPARγ−/− mice are protected against steatosis.88,89 However, in humans PPARγ expression was shown to be reduced in NASH patients, whereas PPARγ agonists improve liver enzymes and some histological features. Activation of PPARα and γ may also have antiinflammatory effects and PPARs play a key role HM781-36B in vivo in HSC biology (see above).
Despite the beneficial effects on metabolic parameters such as insulin resistance and hepatic triglyceride contents, the effects of glitazones on histological features of NASH and liver fibrosis in recent long-term studies were rather disappointing90-92 (Supporting Table 4). More recently, PPARδ activation was reported to reduce liver fat content, probably by increasing hepatic glucose catabolism together with enhanced muscle β-oxidation and lowering hepatic SREBP1c activation.93 check details However, no clinically applicable ligands are currently available (Supporting
Table 4). FXR-deficient mice develop hepatic steatosis and hypertriglyceridemia, reflecting the central role of FXR in the regulation of hepatic lipid metabolism.53,59,63 The FXR downstream target SHP also plays an important role in NAFLD, because SHP expression is induced in leptin-deficient (OB−/−) mice and in high-sucrose/high fat diet models of NAFLD, whereas SHP deficiency in OB−/−/SHP−/− double knockout
mice prevented fatty liver.94 SHP deletion increased serum triglyceride levels in OB−/−/SHP−/− mice by way of higher rates of hepatic VLDL-triglycerides secretion due to increased expression of MTP.94 In addition, OB−/−/SHP−/− mice also showed reduced expression of fatty acid uptake Dynein and de novo fatty acid synthesis genes, which could contribute to protection against steatosis.94,95 However, this protective effect of SHP deficiency against obesity and NAFLD in mice contrasts the reported association of SHP defects with increased body weight.95 Stimulation of FXR and/or TGR5 by specific pharmacological ligands has been shown to improve steatosis and associated insulin resistance in several mouse and rat models of obesity and NAFLD.52,59 Despite some promising results in initial pilot studies, ursodeoxycholic acid (UDCA), which is a very weak FXR and TGR ligand,59 has limited therapeutic efficacy in NASH in humans.96 Interestingly, however, UDCA improves hepatic endoplasmic reticulum (ER) stress and insulin sensitivity in mice.97 In addition to SHP, another former orphan NR—LRH-1—may also play a key role in NAFLD.