The role of hepatic peroxisome proliferator-activated receptors (PPARs) inhealth and disease

The liver has long been known to respond to exposure to certain chemicals w ith hyperplasia and proliferation of the peroxisomal compartment. This resp onse is now known to be mediated by specific receptors. The peroxisome prol iferator-activated receptors (PPARs) were cloned 10 years ago, and in that interval, have been found to serve as receptors for a number of endogenous lipid compounds, in addition to the peroxisome proliferators that originall y led to their study. Three receptors, designated the alpha, delta, and gam ma receptors, have been found in mammals. PPAR alpha is the most abundant f orm found in the liver, with smaller amounts of the delta and gamma forms a lso expressed there. Kupffer cells, like other macrophages, appear to expre ss the alpha and gamma isoforms. Hepatic stellate cells are reported to exp ress the gamma isoform. PPAR alpha knock-out mice fail to undergo peroxisom e proliferation when challenged with the proliferators. Moreover, they have severe derangements of lipid metabolism, particularly during fasting, indi cating that normal function of the alpha receptors is needed for lipid home ostasis. 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 PPAR gamma, receptors ma y be important in control of the activation state of the stellate cells, an d their repression or inactivation may predispose to hepatic fibrosis. The first approved drug that specifically activates PPAR gamma, troglitazone, h as rarely been found to cause serious liver injury. Although this is likely to represent an idiosyncratic reaction, the medical community win need to be alert to the possibility that activation or blockade of these receptors may cause hepatic dysfunction.