C-type natriuretic peptide (CNP) in endothelial cells attenuates hepatic fibrosis and inflammation in non-alcoholic steatohepatitis.

ABSTRACT

AIMS: Our previous study revealed that mice transgenic for endothelial-cell-specific overexpression of CNP (E-CNP Tg mice) are protected against the increased fat weight, inflammation, and insulin resistance associated with high-fat diet (HFD)-induced obesity. In addition, E-CNP overexpression prevented abnormal lipid profiles and metabolism and blocked inflammation in the livers of HFD-fed mice. Because obesity, dyslipidemia, and insulin resistance increase the risk of various liver diseases, including non-alcoholic steatohepatitis (NASH), we here studied the role of E-CNP overexpression in the livers of mice in which NASH was induced through feeding of either HFD or a choline-deficient defined l­amino-acid diet (CDAA). MAIN METHODS: Wild-type (Wt) and E-CNP Tg mice were fed either a standard diet or HFD for 25 weeks or CDAA for 10 weeks. We then assessed hepatic and serum biochemistry; measured blood glucose during glucose tolerance test (GTT) and insulin tolerance test (ITT); evaluated hepatic fibrosis and inflammation; and performed hepatic histology and gene expression analysis. KEY FINDINGS: Serum triglycerides, total cholesterol, non-esterified fatty acids, asparagine transaminase, glucose tolerance, and insulin resistance were ameliorated by CNP overexpression in endothelial cells of HFD-fed E-CNP Tg mice. In addition, hepatic fibrosis and inflammation were decreased in HFD-fed E-CNP Tg mice compared with HFD-fed Wt mice. CDAA-fed E-CNP Tg mice showed improved glycemic control, but liver parameters, fibrosis, and inflammation were remained elevated and equivalent to those in CDAA-fed Wt mice. SIGNIFICANCE: The overexpression of CNP in endothelial cells has anti-fibrotic and anti-inflammatory effects in liver during HFD-induced NASH in mice.