The role of hepatic peroxisome proliferator-activated receptors in health and disease. Liver

Abstract: The liver has long been known to respond to exposure to certain of Medicine, 3Indianapolis Veteran’s Affairs chemicals with hyperplasia and proliferation of the peroxisomal com- Medical Center, Indianapolis, USA and 2Alcohol partment. This response is now known to be mediated by specific recep- Research Center & Gastroenterology Unit, tors. The peroxisome proliferator-activated receptors (PPARs) were Department of Clinical Physiopathology, cloned 10 years ago, and in that interval, have been found to serve as University of Florence, Florence, Italy receptors for a number of endogenous lipid compounds, in addition to the peroxisome proliferators that originally led to their study. Three receptors, designated the a, d, and g receptors, have been found in mammals. PPARa is the most abundant form found in the liver, with smaller amounts of the d and g forms also expressed there. Kupffer cells, like other macrophages, appear to express the a and g isoforms. Hepatic stellate cells are reported to express the g isoform. PPARa knock-out mice fail to undergo peroxisome proliferation when challenged with the proliferators. Moreover, they have severe derangements of lipid metabolism, particularly during fasting, indicating that normal function of the alpha receptors is needed for lipid homeostasis. This in turn suggests that inadequate PPAR-mediated responses may contribute to abnormal fatty acid metabolism in alcoholic and non-alcoholic steatohepatitis. Recent information suggests that PPARg receptors may be important in control of the activation state of the stellate cells, and their repression or inacti- Key words: peroxisome – fatty acids – vation may predispose to hepatic fibrosis. The first approved drug that metabolism – receptor – liver injury – specifically activates PPARg, troglitazone, has rarely been found to cause steatohepatitis serious liver injury. Although this is likely to represent an idiosyncratic David Crabb, Emerson Hall Room 317, 545 reaction, the medical community will need to be alert to the possibility Barnhill Drive, Indianapolis, IN 46202, USA that activation or blockade of these receptors may cause hepatic dysfunc- Received and accepted for publication 3 tion.