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In this study, we investigated hepatic fibrogenesis caused by long-term thioacetamide (TAA) administration in ob/ob mice, a naturally occurring leptin deficient animal. In the lean littermates, prominent hepatic fibrosis, as well as positive staining for ␣ smooth muscle actin (␣-SMA), was induced by treatment with TAA (200 g/g, IP, 3 times per week) for 4 to 8 weeks as expected. In sharp contrast, almost no hepatic fibrosis developed in ob/ob mice given the equivalent doses of TAA, where specific staining for ␣-SMA barely was detected. Induction of ␣1(I) procollagen mRNA caused by TAA also was prevented in ob/ob mice almost completely. Further, transforming growth factor ␤ (TGF-␤) mRNA was increased in the liver after TAA treatment for 4 weeks in lean littermates, which also was prevented in ob/ob mice. Interestingly, fibrotic septa in the hepatic lobules, as well as increases in ␣1(I) procollagen mRNA, was observed in ob/ob mice, when they were injected with recombinant murine leptin (1 g/g daily) in combination with TAA treatment. Leptin per se did not cause any fibrotic changes in the liver in ob/ob mice. These findings clearly indicated that leptin deficiency is responsible for the resistance to TAA-induced profibrogenic responses in ob/ob mice. R egardless of etiologies, progression of hepatic fibrosis is a major and common problem in chronic liver diseases. Activation of hepatic stellate cells (HSCs, also called Ito cells, lipocytes, and fat-storing cells) is now believed to be the essential event in hepatic fibrogenesis, because HSCs transactivate to myofibroblast-like cells that produce a large, excess amount of extracellular matrix proteins (e.g., fibrillar collagen, fibronectin, laminin, proteoglycans) in injured liver. 1 On the other hand, emerging attention has been paid on the relationship between obesity and progression of chronic liver diseases. Lines of evidence indicated that obesity is an important risk factor for the progression of a variety of liver diseases including chronic hepatitis C, 2 alcohol-induced liver diseases 3 and nonalcoholic fatty liver diseases. 4 Especially, nonalcoholic steatohepatitis often is found in patients with obesity and type 2 diabetes, 4 suggesting the close correlation between obesity, impaired glucose tolerance and hepatic injury. However, the mechanisms by which obesity facilitates hepatic inflammation, fibrogenesis, or both, remain unclear.Leptin, an obese gene product, is a 16-kd peptide hormone that is produced predominantly from adipose tissue. 5 Original findings by Friedman et al. 6 indicate that leptin plays a crucial role in the regulation of appetite and the size of body fat mass, mainly through actions on central nervous system. Indeed, naturally occurring knockout animals of leptin and leptin receptor genes, known as ob/ob mice and db/db mice, respectively, present remarkable obesity and impaired glucose tolerance. 7,8 Further, a long-form leptin receptor has been identified predominantly in hypothalamic neurons, 9,10 which activates the intracellula...

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Emerging evidence has suggested a critical role of leptin in hepatic inflammation and fibrogenesis, however, the precise mechanisms underlying the profibrogenic action of leptin in the liver has not been well elucidated. Therefore, the present study was designed to investigate the expression and functions of leptin receptors (Ob-R) in hepatic sinusoidal cells. Hepatic stellate cells (HSCs), Kupffer cells and sinusoidal endothelial cells (SECs) were isolated from rat livers by in situ collagenase perfusion followed by differential centrifugation technique, and expression of Ob-Ra and Ob-Rb, short and long Ob-R isoforms, respectively, were analyzed by RT-PCR. Ob-Ra mRNA was detected ubiquitously in HSCs and SECs. In contrast, Ob-Rb was detected clearly only in SECs and Kupffer cells, but not in 7-day cultured HSCs. Indeed, tyrosine-phosphorylation of STAT-3, a downstream event of Ob-Rb signaling, was observed in SECs, but not in HSCs, 1 hr after incubation with leptin. Further, leptin increased AP-1 DNA binding activity and TGF-beta 1 mRNA levels in Kupffer cells and SECs, whereas leptin failed to increase TGF-beta 1 mRNA in HSCs. These findings indicated that SECs and Kupffer cells, but not HSCs, express functional leptin receptors, through which leptin elicits production of TGF-beta 1. It is hypothesized therefore that leptin, produced systemically from adipocytes and locally from HSCs, up-regulates TGF-beta 1 thereby facilitate tissue repairing and fibrogenesis in the sinusoidal microenvironment.

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