Nonalcoholic steatohepatitis (NASH) is a disorder characterized by hepatic steatosis, inflammation, and fibrosis. Leptin is an adipocyte-derived antiobesity hormone that in rodents prevents "lipotoxicity" by limiting triglyceride accumulation and also regulates matrix deposition (fibrosis) during wound healing. We therefore determined serum leptin levels in patients with NASH to determine whether relationships existed between leptin levels and severity of hepatic steatosis or fibrosis. We used a radioimmunoassay to determine serum [total] leptin concentrations in 27 men and 20 women with NASH and 47 controls matched for gender and body mass index (BMI; and partly for age). Serum leptin values were correlated with hepatic steatosis, fibrosis, and inflammation (each categorized semiquantitatively on liver histology), and with anthropometric indices, serum lipids, glucose, insulin, c-peptide, and alanine aminotransferase (ALT) levels. Compared with the controls, mean serum leptin levels were raised in both men and women with NASH (men 14 ؎ 11 ng/mL vs. 7.2 ؎ 4.1 ng/mL, P ؍ .003; women 35 ؎ 16 ng/mL vs. 15 ؎ 8.2 ng/mL, P < .001). Leptin values correlated with serum c-peptide levels but not with BMI. In a multivariate analysis, serum leptin (P ؍ .027), serum c-peptide (P ؍ .001), and age (P ؍ .027) were selected as independent predictors of the severity of hepatic steatosis. However, serum leptin was not an independent predictor of hepatic inflammation or fibrotic severity. In conclusion, hyperleptinemia occurs in NASH and is not explained simply by gender, obesity, or the presence of type 2 diabetes. Furthermore, leptin levels correlate directly with the severity of hepatic steatosis but not with inflammation or fibrosis. We propose that the relationship between leptin and steatosis reflects a pathogenic role of leptin in hepatic insulin resistance and/or a failure of the antisteatotic actions of leptin ("peripheral leptin resistance"). (HEPATOLOGY 2002;36:403-409.) L eptin is the 16-kd peptide product of the ob gene. It was initially characterized as a regulator of body weight and energy expenditure. 1 It seems unlikely that the principal function of leptin would be to limit obesity, because starvation and famine rather than food excess have typified much of human evolution. 2 From animal studies, it is now emerging that one of the main physiological roles of leptin is to prevent lipid accumulation in nonadipose sites, such as the myocardium, skeletal muscle, pancreas, and liver, 3,4 a concept referred to as "lipotoxicity."Although lipotoxicity is not currently defined as a distinct entity in humans, it has been demonstrated in several experimental models. 3,4 Thus, whereas rodents fed a highfat diet (60% of energy content) develop steatosis, 3 lipid accumulation in the liver (1-to 2.7-fold increase) is disproportionately less than the increase in body fat (ϳ150-fold). By contrast, leptin-deficient (ob/ob) mice and leptin-unresponsive (db/db, fa/fa) rats that received only a 6% fat diet developed extre...
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