Nonalcoholic fatty liver disease is a clinicopathological syndrome that is closely associated with obesity and other metabolic syndrome features (1).
Recent research has shown that adiponectin is a novel adipocyte-derived hormone with antidiabetic and antiatherogenic properties (2). In humans, plasma adiponectin levels are significantly lower in insulin-resistant states (2), thus suggesting that this adipocytokine is an important marker of the metabolic syndrome. Administration of adiponectin to mice has been shown to produce beneficial effects on glucose metabolism (2). Furthermore, administration of this protein was also effective in ameliorating liver biopsy features and liver test results in ob/ob mice (3). Accordingly, after controlling for age, sex, and BMI, hypoadiponectinemia was significantly correlated with increased serum alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) levels in overweight (4) and obese (3) healthy individuals. Although it was hypothesized that such a relationship was probably due to concomitant hepatosteatosis, no morphologic liver examinations were performed in any of these studies. Therefore this hypothesis remains to be demonstrated.
In this pilot study, we enrolled 38 obese healthy individuals (28 men and 10 women, age 46 ± 2 years) with an alcohol consumption of <20 g/day. Subjects with ultrasonographically diagnosed hepatic steatosis (n = 26) had markedly lower plasma adiponectin (by enzyme-linked immunosorbent assay) concentrations than those (n = 12) without hepatic steatosis (5.3 ± 3 vs. 10.1 ± 4 μg/ml [mean ± SD], P < 0.001); the former also had significantly higher values for BMI (34 ± 2 vs. 32 ± 1 kg/m2), waist-to-hip ratio (1.07 ± 0.02 vs. 0.99 ± 0.03), homeostasis model assessment of insulin resistance (6.42 ± 1 vs. 4.34 ± 1), plasma triglycerides (3.1 ± 1 vs. 2.2 ± 1 mmol/l), ALT (57 ± 6 vs. 38 ± 5 units/l), and GGT (70 ± 5 vs. 45 ± 4 units/l) and tended to have lower HDL cholesterol. Age, sex, blood pressure, and other liver function tests were comparable between the groups. Importantly, the significant differences in plasma adiponectin concentrations that were observed between the groups were only slightly weakened after adjustment for age, sex, BMI, waist-to-hip ratio, homeostasis model assessment of insulin resistance, and plasma lipids. In multivariate analyses, hypoadiponectinemia significantly predicted (P < 0.001) the presence of hepatic steatosis and the increased levels of GGT and ALT, independently of potential confounders, including insulin resistance and measures of total and regional adiposity.
Thus, these results show that hypoadiponectinemia is closely associated with nonalcoholic hepatic steatosis in obese healthy individuals, thus suggesting that hypoadiponectinemia might be, at least partly, responsible for hepatic steatosis and liver test abnormalities found in these subjects. Interpretation of our results, however, requires care because of the relatively small number of patients. Future studies using larger cohorts will be needed to validate this hypothesis.
This clinical finding, however, is consistent with a recent study demonstrating that adiponectin administration was effective in alleviating obesity-induced hepatomegaly, steatosis, and serum ALT abnormality in mice (3). The potential hepatoprotective mechanisms include induction of hepatic fatty acid oxidation, inhibition of fatty acid synthesis, and suppression of tumor necrosis factor-α production in the liver. Therefore, in addition to its antidiabetic and antiatherogenic potentials, adiponectin or its agonists may represent a novel agent for the treatment of liver diseases.
