Leptin iNOS Tenascin C Liver fibrosis Inflammation
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Becerril, S. (Sara); Rodriguez, A. (Amaia); Catalan, V. (Victoria); et al. "iNOS gene ablation prevents liver fibrosis in leptin-deficient ob/ob mice". Genes. 10 (3), 2019, 184
The role of extracellular matrix (ECM) remodeling in fibrosis progression in nonalcoholic
fatty liver disease (NAFLD) is complex and dynamic, involving the synthesis and degradation
of different ECM components, including tenascin C (TNC). The aim was to analyze the influence
of inducible nitric oxide synthase (iNOS) deletion on inflammation and ECM remodeling in the
liver of ob/ob mice, since a functional relationship between leptin and iNOS has been described.
The expression of molecules involved in inflammation and ECM remodeling was analyzed in
the liver of double knockout (DBKO) mice simultaneously lacking the ob and the iNOS genes.
Moreover, the effect of leptin was studied in the livers of ob/ob mice and compared to wild-type
rodents. Liver inflammation and fibrosis were increased in leptin-deficient mice. As expected,
leptin treatment reverted the obesity phenotype. iNOS deletion in ob/ob mice improved insulin
sensitivity, inflammation, and fibrogenesis, as evidenced by lower macrophage infiltration and
collagen deposition as well as downregulation of the proinflammatory and profibrogenic genes
including Tnc. Circulating TNC levels were also decreased. Furthermore, leptin upregulated TNC
expression and release via NO-dependent mechanisms in AML12 hepatic cells. iNOS deficiency in
ob/ob mice improved liver inflammation and ECM remodeling-related genes, decreasing fibrosis, and
metabolic dysfunction. The activation of iNOS by leptin is necessary for the synthesis and secretion
of TNC in hepatocytes, suggesting an important role of this alarmin in the development of NAFLD.