72,73 Because HNF4α has no therapeutic ligand and therefore is st

72,73 Because HNF4α has no therapeutic ligand and therefore is still of limited clinical relevance, it is not further discussed here (review74). HDL-cholesterol creates a net flux of cholesterol from the periphery back to the liver, where it is excreted either as free cholesterol or bile acids into bile, a process termed “reverse cholesterol transport.” Expression of both

apoAI and apoAII (the structural apolipoproteins of HDL particles) is under the control of HNF4α.75 PPARα activation by fibrates increases levels of apoAI and apoAII, and thus HDL in humans.75 In contrast, mouse and rat apoAI is paradoxically repressed by fibrates,75 which needs http://www.selleckchem.com/products/Lapatinib-Ditosylate.html to be taken into account when interpreting experimental studies in rodents. LXRα was also found to repress apoAI synthesis, further adding to concerns on the potential utility of LXR agonists in the treatment of dyslipidemia.76 Finally, PPARα/γ and RXR77 as well as LXR14,77 up-regulate ATP binding cassette 1 (ABCA1) expression

in macrophages and thus promote cholesterol efflux to HDL. Bile acid-binding sequestrants/resins such as cholestyramine increase HDL-cholesterol.78 Conversely, accumulation of intrahepatic bile acids in cholestatic PFIC patients lowers,77 whereas biliary diversion again increases HDL-cholesterol levels.79 These findings can be explained by bile acid-mediated activation of FXR resulting in repression of apoAI by way of a negative FXR response element.77 In line with this, FXR-deficient mice are hypercholesterolemic due to an increase of HDL-cholesterol levels.80 These findings may need to be considered Selleckchem Erlotinib when applying FXR ligands for treatment of dyslipidemia. Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum ranging from simple fatty liver to nonalcoholic streatohepatitis (NASH) cirrhosis and hepatocellular carcinoma (HCC).81 Apart from the inherent mafosfamide risk for progression of liver disease, NAFLD has recently been identified as an independent risk factor for endothelial dysfunction

and cardiovascular death.81 NRs control fatty acid flux from peripheral white adipose tissue to the liver and regulate several critical metabolic steps involved in the pathogenesis of NAFLD, including fat storage, lipolysis, export, uptake, and oxidation. Surprisingly, little information is available about hepatic and WAT NR alterations in NAFLD patients and their role in progression from bland fatty liver to more aggressive NASH. As gatekeepers of fatty acid flux from adipose tissue to the liver and key regulators of hepatic metabolism, inflammation, and fibrosis, NRs could play a central role in this progression. PPARγ is expressed at very low levels in normal liver (mainly in Kupffer cells), but is increased in animal models with insulin resistance and fatty liver.82,83 WAT expandability may be a critical determinant of preventing fatty acid overflux to ectopic storage sites such as liver.

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