Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endogenous peptide C-type natriuretic peptide (CNP) binds its receptor, guanylyl cyclase B (GCB), and is expressed by endothelial cells in diverse tissues. Because the endothelial cells of visceral adipose tissue have recently been reported to play a role in lipid metabolism and inflammation, we investigated the effects of CNP on features of obesity by using transgenic (Tg) mice in which CNP was placed under the control of the Tie2 promoter and was thus overexpressed in endothelial cells (E-CNP). Here we show that increased brown adipose tissue thermogenesis in E-CNP Tg mice increased energy expenditure, decreased mesenteric white adipose tissue (MesWAT) fat weight and adipocyte hypertrophy, and prevented the development of fatty liver. Furthermore, CNP overexpression improved glucose tolerance, decreased insulin resistance, and inhibited macrophage infiltration in MesWAT, thus suppressing pro-inflammation during high-fat diet-induced obesity. Our findings indicate an important role for the CNP produced by the endothelial cells in the regulation of MesWAT hypertrophy, insulin resistance, and inflammation during high-fat diet-induced obesity.
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PMID:Overexpression of C-type Natriuretic Peptide in Endothelial Cells Protects against Insulin Resistance and Inflammation during Diet-induced Obesity. 2885 70

Endothelial dysfunction and reduced nitric oxide (NO) signaling are a key element of the pathophysiology of nonalcoholic steatohepatitis (NASH). Stimulators of soluble guanylate cyclase (sGC) enhance NO signaling; have been shown preclinically to reduce inflammation, fibrosis, and steatosis; and thus have been proposed as potential therapies for NASH and fibrotic liver diseases. Praliciguat, an oral sGC stimulator with extensive distribution to the liver, was used to explore the role of this signaling pathway in NASH. We found that sGC is expressed in hepatic stellate cells and stellate-derived myofibroblasts, but not in hepatocytes. Praliciguat acted directly on isolated hepatic stellate cells to inhibit fibrotic and inflammatory signaling potentially through regulation of AMPK and SMAD7. Using in vivo microdialysis, we demonstrated stimulation of the NO-sGC pathway by praliciguat in both healthy and fibrotic livers. In preclinical models of NASH, praliciguat treatment was associated with lower levels of liver fibrosis and lower expression of fibrotic and inflammatory biomarkers. Praliciguat treatment lowered hepatic steatosis and plasma cholesterol levels. The antiinflammatory and antifibrotic effects of praliciguat were recapitulated in human microtissues in vitro. These data provide a plausible cellular basis for the mechanism of action of sGC stimulators and suggest the potential therapeutic utility of praliciguat in the treatment of NASH.
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PMID:sGC stimulator praliciguat suppresses stellate cell fibrotic transformation and inhibits fibrosis and inflammation in models of NASH. 3108 47