NASH—hepatic metabolism and not simply the metabolic syndrome

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are highly prevalent diseases, and it is estimated that a quarter of the American adult population currently has NAFLD.1-3 Furthermore, 20% to 30% of patients with NAFLD will develop fibrosing steatohepatitis that may progress to cirrhosis, end-stage liver disease, and hepatocellular carcinoma.1,2 Obesity has reached epidemic proportions in America, effecting 25% to 30% of the population, and this parallels the rise in insulin-resistant states such as the metabolic syndrome and type 2 diabetes.4 A growing body of literature shows the close relationship of steatohepatitis with the metabolic syndrome, characterized by abdominal obesity, insulin resistance with or without frank hyperglycemia, dyslipidemia, and hypertension, and several recent studies document the association of NASH with the metabolic syndrome.4-9 Nevertheless, this association is not universal. NASH can occur in patients who do not have evidence of insulin resistance, most individuals with type 2 diabetes do not have NASH, and the prevalence of the metabolic syndrome is far greater than the prevalence of NASH. In addition, data from patients with polycystic ovarian syndrome indicate that only 5% of this insulin-resistant population have evidence of elevated serum alanine aminotransferase (ALT) levels, and although an elevated ALT may be a relatively insensitive marker for NASH, the 5% incidence of elevated serum ALT levels in a universally insulin-resistant population strongly suggests that most polycystic ovarian syndrome patients do not have NASH.10 Thus, there is much more to the pathogenesis of NASH than simply insulin resistance. A current concept in the pathogenesis of NASH involves a “two-hit” hypothesis in which an initial metabolic disturbance causes steatosis and a second pathogenic stimulus causes oxidative stress, reactive oxygen species, lipid peroxidation, and a resultant steatohepatitis. However, like diabetes, NASH is almost certainly a polygenic disease affected by environmental factors and stressors, with disease pathogenesis related to “multiple hits. ” Although the metabolic syndrome and insulin resistance are important risk factors for the development of NASH, our current knowledge of the genetic, biochemical, metabolic, inflammatory, endocrine, and environmental mechanisms responsible for the pathogenesis of NASH is poorly understood. In this issue of HEPATOLOGY, studies by Ip et al.11 and Lettéron et al.12 employing different experimental models of steatosis and steatohepatitis, provide important insights into additional hepatic metabolic factors that are of potential importance for the development and progression of NASH. Ip et al.11 employ a methionine-choline deficient (MCD) dietary model of fibrosing steatohepatitis to show the importance of peroxisome proliferator-activated receptor (PPAR) signaling in the development of fibrosing steatohepatitis. PPARagonist drugs include clofibrate and other fibrates that are commonly used clinically for the treatment of hyperlipidemia. Although PPARagonists may potentially increase oxidative stress by inducing expression of the hepatic P450 enzymes Cyp4a10 and Cyp4a14, when mice were fed an MCD diet, mice treated with the PPARagonist Wy-14,643 developed significantly less steatohepatitis, markedly lower ALT levels, and less lipid peroxidation. This occurred despite a marked increase of the Cyp4a enzymes. This unexpected finding probably occurs because treatment with the PPARagonist Wy-14,643 reduced hepatic triglycerides and steatosis with associated alterations of several enzymes in the peroxisomal -oxidation pathway and liver fatty acid binding protein. Furthermore, the investigators treated PPARnull mice with the MCD diet and showed that they developed more severe steatohepatitis than wild-type mice, further indicating a role of PPARsignaling in the pathogenesis of steatohepatitis. In another important study, Lettéron et al.12 treated mice with pharmacologic agents (amiodarone, tetracycline, pirprofen, tianepine) that induce hepatic steatosis and investigated the effects on microsomal triglyceride transfer protein, an endoplasmic reticulum protein that Abbreviations: NAFLD, nonacoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; ALT, alanine aminotransferase; MCD, methionine-choline–deficient diet; PPAR, peroxisome proliferator-activated receptor ; VLDL, very low density lipoprotein; PC, phosphatidylcholine; AOX, acyl-CoA oxidase. From the Division of Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL. Address reprint requests to: Richard M. Green, M.D., Chief, Division of Hepatology, Northwestern University Feinberg School of Medicine, Searle 10-555, 303 E. Chicago Ave., Chicago, IL 60611. E-mail: r-green2@northwestern.edu; fax: 312-908-6192. Copyright © 2003 by the American Association for the Study of Liver Diseases. 0270-9139/03/3801-0003$30.00/0 doi:10.1053/jhep.2003. 50325