Peroxisome proliferator chemicals, acting via the peroxisome proliferator-activated receptor-␣ (Ppar␣), are potent hepatic mitogens and carcinogens in mice and rats. To test whether Ppar␣ 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 Ppar␣-null mice. Ppar␣-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 G 1 /S checkpoint regulator genes Ccnd1 and cMyc and increased expression of the IL-1␤ cytokine gene. Hepatic expression of Ccnd1, cMyc, IL-1r1, and IL-6r was induced in wild-type mice, but not Ppar␣-null mice, after acute exposure to the potent Ppar␣ agonist Wy-14,643, indicating a role for Ppar␣ in regulating the expression of these genes. Expression of the fatty acid -hydroxylase gene Cyp4a14, a commonly used indicator gene for Ppar␣ 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 Ppar␣ gene. In conclusion, liver regeneration in Ppar␣-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.) P eroxisome proliferator (PP) xenobiotics are potent hepatic mitogens and carcinogens in mice and rats. 1 Increases in hepatocyte replication and tumor formation after PP exposure require activation of the peroxisome proliferator-activated receptor-␣ (Ppar␣). 2 Many transcriptional targets of Ppar␣ have been identified, but none have direct roles in regulating cell proliferation or apoptosis. One of the most effective models for studying hepatocellular proliferation is liver regeneration following hepatocellular loss because of partial hepatectomy (PH) or chemical damage. 3 In the original technique for PH described by Higgins and Anderson in 1931, 4 resection of 70% of the hepatic mass of a rat results in 95% of the remaining hepatocytes rapidly entering the cell cycle. DNA synthesis follows about 12 to 14 hours after resection and reaches a maximum activation at 24 hours. These events occur about 20 hours later in mice. The original mass of the liver is restored within 7 days, with most of the recovery occurring by 3 days. 4 The signals that stimulate and maintain this process are not entirely clear but include the transcriptional activation of several groups of genes in a distinct temporal order. 3,[5][6][7] First, hepatocytes must be primed, presumably by cytokines, to respond to various growth factors. After priming, transition from G 0 to G 1 phases of the cell cycle requires induction of immediate-early class genes, which begins at about 30 minutes post-PH and lasts for about 4 hours. Progression of hepatocytes in vivo through late G 1 phase requires gr...