Nonalcoholic fatty liver disease: pathogenesis and potential for nuclear receptors as therapeutic targets.
Nonalcoholic fatty liver disease (NAFLD) is a consequence of insulin resistance encompassing a spectrum that extends from simple hepatic steatosis through to nonalcoholic steatohepatitis (NASH), a condition that may progress to cirrhosis with its associated complications. A subset of nuclear receptors act as intracellular sensors for cholesterol metabolites, free fatty acids, and a range of other lipophilic molecules with pivotal roles in energy homeostasis and inflammation. These receptors represent attractive drug targets for the management of NAFLD and NASH as well as related conditions such as type 2 diabetes and the broader metabolic syndrome. To date, human studies have concentrated on peroxisome proliferator-activated receptor (PPAR) agonists, particularly those directed at PPARgamma. However, these drugs have significant limitations, so alternate approaches to nuclear receptor targeting are being explored.
George
Jacob
J
Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Westmead Hospital, Westmead NSW 2145, Australia.
Liddle
Christopher
C
D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018160:Receptors, Cytoplasmic and Nuclear