An adipocentric view of liver fibrosis and cirrhosis

Liver fibrosis is the consequence of chronic or repeated liver injury caused by hepatotoxic agents like alcohol and viruses, as well as immune and congenital metabolic disorders. Nonalcoholic fatty liver disease (NAFLD), caused by obesity and abnormal lipid metabolism, may be the latest known cause of liver fibrosis and cirrhosis. Furthermore, NAFLD with obesity can provide a terrain in which alcoholic and viral liver diseases, such as chronic hepatitis C, are prone to cause liver cirrhosis. Insulin, insulin-like growth factor (IGF)-1, peroxisome proliferator-activated receptors (PPARs), leptin, adiponectin, and preadipocyte factor-1/delta-like1 (Pref-1/dlk1) are hormones, growth factors, nuclear receptors, and cytokines that are actively involved in lipid metabolism. They share common target cells important in liver fibrosis, i.e., hepatic stellate cells (HSCs). Activation of HSCs is known to initiate and perpetuate liver fibrosis. Insulin and IGF-1 stimulate HSC activation and collagen production in vitro. However, IGF-1 alleviates liver fibrosis in vivo. Ligands of PPARγ inhibit HSC activation and collagen synthesis in vivo and in vitro, and are helpful in decreasing liver fibrosis. But ligands of PPARβ enhance proliferation of HSCs. Leptin is profibrogenic, and liver fibrosis is decreased in leptin- or leptin receptor-deficient mice. Adiponectin is, on the contrary, anti-fibrogenic. Extensive liver fibrosis may develop in adiponectin-knockout mice and is alleviated by administration of recombinant adiponectin. Pref-1/dlk1 is implicated in fibrogenesis of the liver through its modulation of HSCs. The use of such biologically active molecules in lipid metabolism as ligands of PPARγ and adiponectin might not help slim down a patient on the whole, but can potentially be used to halt the progression of liver fibrosis. Weight reduction, a strategy for controlling obesity and metabolic syndromes, may also be a tool for decreasing NAFLD and alleviating liver cirrhosis.