8.A.94. The Adiponectin (Adiponectin) Family
Adiponectin is an important adipokine involved in the control of fat metabolism and insulin sensitivity, with direct anti-diabetic, anti-atherogenic and anti-inflammatory activities (Yamauchi et al. 2001). It stimulates AMPK phosphorylation and activation in the liver and skeletal muscle, enhancing glucose utilization and fatty-acid consumption. It antagonizes TNF-alpha by negatively regulating its expression in various tissues such as liver and macrophages, and also by counteracting its effects. It inhibits endothelial NF-kappa-B signaling through a cAMP-dependent pathway. It may also play a role in cell growth, angiogenesis and tissue remodeling by binding and sequestering various growth factors with distinct binding affinities, depending on the type of complex, LMW, MMW or HMW (Yamauchi et al. 2001).
Obesity is a major risk factor for liver fibrosis, associated with low levels of adiponectin. Adiponectin has antifibrogenic activity protecting from liver fibrosis, which is mainly driven by activated hepatic stellate cells (HSC). Aquaporins allow the movement of water and, in cases of aquaglyceroporins (AQPs), of glycerol that is needed in quiescent HSC for lipogenesis. Expression of various AQPs in liver is altered by obesity. Tardelli et al. 2017 identified obesity-associated factors that are related to HSC AQP expressional activation and lipid storage. Correlations between serum adipokine levels and hepatic AQP gene expression were analyzed from a cohort of obese patients. AQP and fibrotic gene expression was determined in a HSC line (LX2) and in a hepatocyte cell line (HepG2) after stimulation with adiponectin using quantitative real-time polymerase chain reaction. It was found that serum adiponectin correlated with liver AQP3, AQP7, AQP9 gene expression. In vitro, adiponectin induced upregulation of AQP3 gene and AQP3 protein expression in human HSCs, but not in hepatocytes, while AQP7, AQP9 remained undetectable. Accordingly, HSC stimulated with adiponectin increased glycerol uptake, lipogenic gene expression, and lipid storage while downregulating activation/fibrosis markers. Thus, adiponectin is a potent inhibitor of HSC activation and induces AQPs expression.