Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease

Background/Aims

Data from animal models of fibrosis and fatty liver suggest that leptin may mediate the profibrogenic responses in the liver, but the association of leptin and liver fibrosis in human nonalcoholic fatty liver disease (NAFLD) remains undefined. We aimed at determining the relation between leptin and liver fibrosis in human NAFLD.

Methods

Human plasma leptin and several indicators of insulin resistance were measured in 88 NAFLD patients and matched controls.

Results

Leptin levels were significantly greater in patients with more advanced fibrosis (P=0.005). By multivariate analysis, the significant association between leptin and fibrosis was abolished (adjusted P=0.3) when controlling for confounders including age, gender, BMI, diabetes and insulin resistance. Only age (adjusted P=0.006) and insulin sensitivity (adjusted P=0.04) correlated significantly with fibrosis stage. A second liver biopsy was performed in 39 out of the 88 patients at 27.9±16 months. Leptin levels were not significantly different between patients who had fibrosis progression (n=10) and those who did not (n=29).

Conclusions

In human NAFLD, no relationship between leptin levels and fibrosis stage was demonstrated. The correlation of leptin and fibrosis severity seems to be an indicator of the factors that determine leptin production.

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-R_L) 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-R_L [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.