98 Interestingly, phospholipids are highly enriched within the nucleus.99 Screening FK506 solubility dmso of native LRH-1 ligands identified unusual phospholipids with antidiabetic and antisteatotic properties. It is attractive to speculate that this could explain the therapeutic effects of lecithin and other lipids in these disorders. Finally, the xenobiotic NRs, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), may also have important roles in the regulation of the metabolism of fatty acids, lipids, and glucose (Supporting Table 4). This could account for some of the metabolic side effects (e.g., hepatic steatosis) of drugs activating PXR and or CAR (e.g., anticonvulsants,

antidepressants). NRs such as CAR control CYP expression, which could contribute to oxidative stress in the progression to NASH.100 In line with this concept, methionine and choline-deficient diet increased CAR activation and liver inflammation as well as lipid peroxidation in wildtype mice, whereas CAR knockout mice were protected.100 ABC294640 supplier Future studies will have to unravel the connections between networks as well as to design an appropriate mouse model recapitulating

the course of the human disease. Another NR with potential relevance for treatment of NAFLD is VDR, because low levels of vitamin D have been linked to NAFLD in children101 as well as insulin resistance (IR) and metabolic syndrome (recently reviewed102). NRs play a central role in the regulation of bile acid synthesis,

metabolism, and transport. Carnitine dehydrogenase Under cholestatic conditions with high intracellular bile acid load, NRs mediate a coordinated response aimed at protecting hepatocytes from toxic bile acids (Supporting Table 5). Mice lacking the NRs FXR, PXR, and CAR are more vulnerable towards bile acids exposure and cholestatic injury.80,103-105 Genetic variants of FXR may determine susceptibility to gallstones disease106 and cholestasis of pregnancy,107,108 whereas PXR variants have been linked to progression of chronic cholangiopathies such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).109,110 Stimulation of the bile acid detoxification machinery with drugs targeting FXR, PXR, and CAR reduces cholestasis and its complications such as pruritus. Such substances are already used in daily clinical practice (e.g., “enzyme inducers” such as rifampicin), whereas others are currently tested in clinical trials and many more are expected to enter clinical trials in the near future. Understanding NR function has therefore not only significantly increased our insights into physiology and pathophysiology of bile acid metabolism but also led to development of NR ligands for the treatment of cholestasis. FXR is the key intracellular bile acid sensor regulating a vast majority of processes involved in bile acid formation, transport, and detoxification (Supporting Table 5). One of FXR’s main functions is limiting hepatocellular bile acid overload.