Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice



Peroxisome proliferator chemicals, acting via the peroxisome proliferator-activated receptor-α (Pparα), are potent hepatic mitogens and carcinogens in mice and rats. To test whether Pparα is required for hepatic growth in response to other stimuli, we studied liver regeneration and hepatic gene expression following partial hepatectomy (PH) of wild-type and Pparα-null mice. Pparα-null mice had a 12- to 24-hour delay in liver regeneration associated with a delayed onset and lower peak magnitude of hepatocellular DNA synthesis. Furthermore, these mice had a 24-hour lag in the hepatic expression of the G1/S checkpoint regulator genes Ccnd1 and cMyc and increased expression of the IL-1β cytokine gene. Hepatic expression of Ccnd1, cMyc, IL-1r1, and IL-6r was induced in wild-type mice, but not Pparα-null mice, after acute exposure to the potent Pparα agonist Wy-14,643, indicating a role for Pparα in regulating the expression of these genes. Expression of the fatty acid ω-hydroxylase gene Cyp4a14, a commonly used indicator gene for Pparα activation, was strongly induced in wild-type mice after hepatectomy, suggesting that altered hepatocyte lipid processing may also contribute to the impaired regeneration in mice lacking the Pparα gene. In conclusion, liver regeneration in Pparα-null mice is transiently impaired and is associated with altered expression of genes involved in cell cycle control, cytokine signaling, and fat metabolism. (HEPATOLOGY 2002;36:544-554.)