We have proposed that steatohepatitis results from reactive oxygen species (ROS) acting on accumulated fatty acids to form proinflammatory lipoperoxides. Cytochrome P450 4a (Cyp4a) and Cyp2e1 are potential hepatic sources of ROS. We tested the hypothesis that increasing Cyp4a through activation of peroxisome proliferator-activated receptor ␣ (PPAR␣) should aggravate steatohepatitis produced by feeding a methionine and choline deficient (MCD) diet. Conversely, we assessed dietary steatohepatitis in PPAR␣ ؊/؊ mice that cannot up-regulate Cyp4a. Male wild type (wt) or PPAR␣ ؊/؊ mice (C57BL6 background) were fed the MCD diet with or without Wy-14,643 (0.1% wt/wt), a potent PPAR␣ agonist. Controls were fed the same diet supplemented with methionine and choline. After 5 weeks, wt mice fed the MCD diet developed moderate steatohepatitis and alanine aminotransferase (ALT) levels were increased. Wy-14,643 prevented rather than increased liver injury; ALT levels were only mildly elevated whereas steatohepatitis was absent. Wy-14,643 up-regulated mRNA for liver fatty acid binding protein and peroxisomal ␤-oxidation enzymes (acyl-CoA oxidase, bifunctional enzyme, and ketothiolase), thereby reducing hepatic triglycerides and preventing steatosis. In wt mice, dietary feeding up-regulated Cyp4a14 mRNA 2.7-fold and increased hepatic lipoperoxides compared with controls. Wy-14,643 prevented hepatic lipoperoxides from accumulating despite an 18-fold increase in both Cyp4a10 and Cyp4a14 mRNA. PPAR␣ ؊/؊ mice fed the MCD diet developed more severe steatohepatitis than wt mice, and were unaffected by Wy-14,643. In conclusion, PPAR␣ activation both increases Cyp4a expression and enhances hepatic lipid turnover; the latter effect removes fatty acids as substrate for lipid peroxidation and is sufficiently powerful to prevent the development of dietary steatohepatitis. (HEPATOLOGY 2003;38:123-132.)

In the classical form of alpha1-antitrypsin (AT) deficiency, a point mutation in AT alters the folding of a liver-derived secretory glycoprotein and renders it aggregation-prone. In addition to decreased serum concentrations of AT, the disorder is characterized by accumulation of the mutant alpha1-antitrypsin Z (ATZ) variant inside cells, causing hepatic fibrosis and/or carcinogenesis by a gain-of-toxic function mechanism. The proteasomal and autophagic pathways are known to mediate degradation of ATZ. Here we show that the autophagy-enhancing drug carbamazepine (CBZ) decreased the hepatic load of ATZ and hepatic fibrosis in a mouse model of AT deficiency-associated liver disease. These results provide a basis for testing CBZ, which has an extensive clinical safety profile, in patients with AT deficiency and also provide a proof of principle for therapeutic use of autophagy enhancers. CommentWith an expected prevalence of 0.02%, alpha-1-antitrypsin (AAT) deficiency is one of the most common genetic origins of liver disease in childhood and an important hereditary cause of cirrhosis and hepatocellular carcinoma in adulthood. AAT is an important serine protease inhibitor that is synthesized in the liver (normally as the protease inhibitor M [PiMM] protein), is found in the circulation at substantial levels (>0.8 g/L in serum), and inhibits proteolytic enzymes such as elastase released by neutrophils and macrophages (Fig. 1A). The most common initial clinical presentation of AAT deficiency is chronic obstructive pulmonary disease with typically severe, early-onset panacinar emphysema with a basilar predominance in adults. Emphysema in patients with AAT deficiency is thought to result from increased activity of neutrophil elastase in the lungs, which destroys alveolar septa and other components of the lung interstitium because of the lack of sufficient elastase inhibition by circulating AAT (Fig. 1B).1 The classic form of AAT deficiency is caused by a glutamate-to-lysine exchange at position 342 in the serpin peptidase inhibitor A1 gene [called the protease inhibitor ZZ (PiZZ) genotype], which leads to hepatic synthesis of mutant alpha-1-antitrypsin Z (ATZ) proteins. These mutant ATZ proteins are prone to polymerization and form polymers between the mutated reactive center loop and the beta sheet of the next molecule within the endoplasmatic reticulum (ER) of the hepatocytes. 2 The massive formation of insoluble aggregates of mutant ATZ proteins in the hepatocytic ER results in apoptosis, hepatic inflammation, and fibrosis/cirrhosis and strongly predisposes patients to hepatocellular carcinoma (Fig. 1B). 3 The diagnosis of AAT deficiency is established by low serum AAT levels, which are measured for the screening of suspected patients; this is followed by genotyping (with PiZZ-specific polymerase chain reaction) and protein phenotyping (with isoelectric focusing gel) as verification tests. 4 In liver histology, periodic acid-Schiff-positive, diastaseresistant globules containing ATZ protein polymers in ...