Role of adipocytokines in hepatic fibrogenesis

Abstract

Obesity and insulin resistance are the key factors for progression of hepatic fibrosis in various chronic liver diseases including non-alcoholic steatohepatitis (NASH). Recently it has been shown that leptin plays a pivotal role in development of hepatic fibrosis. Leptin promotes hepatic fibrogenesis through upregulation of transforming growth factor-beta in Kupffer cells and sinusoidal endothelial cells. Further, leptin facilitates proliferation and prevents apoptosis of hepatic stellate cells. There is a paradox, however, in that ob/ob mice and Zucker rats, which are the obese and diabetic strains, had minimal profibrogenic responses in the liver, most likely because they lack leptin and its receptors. To establish a more clinically relevant model to study the mechanism of fibrogenesis under steatohepatitis, fatty changes and profibrogenic responses in the liver caused by methionine-choline deficiency (MCD) were investigated in the KK-A(y) mouse, which is an obese and diabetic strain. KK-A(y) mice developed more severe hepatic steatosis, inflammation and fibrosis induced by an MCD diet as compared to C57Bl/6 controls. Importantly, KK-A(y) mice lack physiological upregulation of adiponectin levels, suggesting that adiponectin plays a pivotal role not only in regulation of insulin sensitivity but also in modulation of inflammatory and profibrogenic responses in dietary steatohepatitis. Collectively, these findings support the hypothesis that the balance of adipocytokine expression is a key regulator for the progression of hepatic fibrosis in the setting of steatohepatitis.

Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice #

“…However, the ob/ob mice liver is not an ideal model to study NASH; due to the lack of leptin in these mice, full activation of stellate cells does not occur, thereby preventing development of steatohepatitis and frank fibrosis. 29,31,32 In accordance, ␣ smooth muscle actin-positive stellate cells were not observed in livers from ob/ob mice (data not shown).…”

“…17 This finding is of particular interest, because inflammation is considered to be a contributing factor to the development of insulin resistance and obesity-related liver injury. 31 NK T cells are suggested to play a protective role in the inflammatory response in hepatic steatosis, and the reduction in NK T cell numbers in humans and animal models are implicated in disease severity. 33 NK T cell numbers have been found to be reduced in ob/ob mouse livers.…”

Mechanisms of Hepatic Fibrogenesis

“…188 Adipokines mediate fibrogenesis and many hepatic manifestations of obesity. 189,190 Specifically, leptin, a circulating adipogenic hormone, promotes stellate cell fibrogenesis and enhances TIMP-1 expression, [191][192][193] which is associated with increased leptin signaling. 191 Concurrently, adiponectin, a counter-regulatory hormone that antagonizes the fibrogenic activity of leptin is reduced in hepatic fibrosis, 194 and mice lacking adiponectin have enhanced fibrosis after toxic liver injury.…”

Physiological potential of cytokines and liver damages

“…[35] Obesity, especially visceral adiposity, is a major risk factor for NASH in humans. [36] Adipose tissue is a source of free fatty acids (FFA) that are delivered to the liver and a depot for triglycerides that are synthesized by hepatocytes and released into the blood. As producers of TNF-α and IL-6, adipocytes are considered a component of the immune system.…”