Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease
Introduction
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide. No proven treatment currently is available for patients with NAFLD, and it is unclear why simple steatosis remains stable in some patients, whereas in others the disease progresses to advanced fibrosis and cirrhosis. Further insights into the mechanisms leading to disease progression are of particular relevance for the development of effective treatment strategies [1].
Leptin, the product of the ob gene, regulates food intake and several metabolic functions [2]. The biological actions of leptin are mediated largely through interaction with the long form (the signaling-competent isoform) of its cognate receptor (Ob-RL) expressed not only in the hypothalamus but also in several peripheral tissues including human hepatic cells [3]. This predicts that leptin will have a wide-ranging influence on metabolism and possibly also liver structure and disease. In human hepatic liver cells, leptin attenuates some insulin-induced activities causing insulin resistance [3], whereas increased insulin resistance represents an almost universal finding in patients with NAFLD suggesting a role for leptin [1], [4], [5].
In particular, leptin seems to play a role in the profibrogenic responses in the liver as shown in in vitro studies and studies performed in animal models of liver fibrosis and fatty liver [6], [7], [8], [9], [10], [11]. Several lines of evidence highlight these profibrogenic activities of leptin in the liver. For instance, activated hepatic stellate cells (HSC), the main hepatic fibrogenic cell type express leptin [6], [7] as well as its receptor, Ob-RL [6], [8] and when treated with leptin these cells show an increased α2(I) collagen gene expression [7], [9]. Injected leptin leads to a greater expression of procollagen type 1, TGF-β1, and α-smooth muscle actin in rats treated with CCl4 or thioacetamide [10], [11]. Furthermore, leptin-deficient (ob/ob) mice and leptin-resistant (fa/fa) rats do not develop liver fibrosis [12]. However, data on leptin and its correlation with liver fibrosis in human NAFLD are scarce. Hence, we aimed at (1) determining the relationship between leptin, insulin resistance, and liver fibrosis in a large number of patients with well-characterized NAFLD; and (2) determining the relationship of leptin levels and degree of insulin resistance with progression of liver fibrosis.
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Patients
The study was approved by the Mayo Institutional Review Board and all patients gave informed consent for participation in medical research. Eighty-eight untreated, consecutive patients with liver biopsy-proven NAFLD who were seen at the Mayo Clinic in Rochester, MN were included in this study. The 88 patients were participants in local or multicentric trials reported previously [13], [14] and enrolled and followed-up from 1991 to 2002. None of these patients was on treatment with metformin,
Characteristics of the patient population
The 88 patients with NAFLD including 57 women and 31 men, had a mean age of 45.3±12.1 years (range 18–69), 61 (69.3%) patients were obese (BMI≥30), and 17 (19.3%) patients suffered from type 2 diabetes mellitus. None of the diabetic patients or controls was on insulin therapy. Leptin levels correlated significantly with BMI in women (r=0.50, P<0.0001) and men (r=0.64, P<0.0001). Leptin levels were significantly higher in women than in men in both the control and NAFLD groups (Fig. 1). Table 1
Discussion
In our study, the correlation of plasma concentration of leptin with severity of liver fibrosis in patients with NAFLD was a reflection of the association between fibrosis severity and variables that determine leptin production such as age, gender, BMI (as a surrogate of amount of body fat), and hyperinsulinemia. The significant association of leptin levels and liver fibrosis by univariate analysis became nonsignificant when leptin levels were adjusted for differences in those confounding
Acknowledgements
The study was supported in part by DK45343 to MDJ. Leon A. Adams is supported by a medical research fellowship from the University of Western Australia.
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☆Presented in part during the annual meeting of the American Association for the Study of Liver Diseases, Boston, MA. October 2002.