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- Title
A Cholecystokinin Receptor Antagonist Halts Nonalcoholic Steatohepatitis and Prevents Hepatocellular Carcinoma.
- Authors
Tucker, Robin D.; Ciofoaia, Victor; Nadella, Sandeep; Gay, Martha D.; Cao, Hong; Huber, Matthew; Safronenka, Anita; Shivapurkar, Narayan; Kallakury, Bhaskar; Kruger, Annie J.; Kroemer, Alexander H. K.; Smith, Jill P.
- Abstract
<bold>Background and Aims: </bold>Nonalcoholic steatohepatitis (NASH) is a common inflammatory liver condition that may lead to cirrhosis and hepatocellular carcinoma (HCC). Risk factors for NASH include a saturated fat diet, altered lipid metabolism, and genetic and epigenetic factors, including microRNAs. Serum levels of cholecystokinin (CCK) are elevated in mice and humans that consume a high-saturated fat diet. CCK receptors (CCK-Rs) have been reported on fibroblasts which when activated can induce fibrosis; however, their role in hepatic fibrosis remains unknown. We hypothesized that elevated levels of CCK acting on the CCK-Rs play a role in the development of NASH and in NASH-associated HCC.<bold>Methods: </bold>We performed a NASH Prevention study and Reversal study in mice fed a saturated fat 75% choline-deficient-ethionine-supplemented (CDE) diet for 12 or 18 weeks. In each study, half of the mice received untreated drinking water, while the other half received water supplemented with the CCK-R antagonist proglumide. CCK-R expression was evaluated in mouse liver and murine HCC cells.<bold>Results: </bold>CCK receptor antagonist treatment not only prevented NASH but also reversed hepatic inflammation, fibrosis, and steatosis and normalized hepatic transaminases after NASH was established. Thirty-five percent of the mice on the CDE diet developed HCC compared with none in the proglumide-treated group. We found that CCK-BR expression was markedly upregulated in mouse CDE liver and HCC cells compared with normal hepatic parenchymal cells, and this expression was epigenetically regulated by microRNA-148a.<bold>Conclusion: </bold>These results support the novel role of CCK receptors in the pathogenesis of NASH and HCC.
- Subjects
HEPATOCELLULAR carcinoma; FATTY liver; CHOLECYSTOKININ; LIVER cells; HEPATIC fibrosis; PULMONARY fibrosis; RNA metabolism; FATTY liver prevention; SULFUR amino acids; BIOLOGICAL models; RESEARCH; HORMONE antagonists; LIVER tumors; LIVER; ANIMAL experimentation; RESEARCH methodology; CELL receptors; RNA; VITAMIN B deficiency; EVALUATION research; MEDICAL cooperation; CELLULAR signal transduction; COMPARATIVE studies; GENES; RESEARCH funding; GLUTAMINE; CELL lines; MICE; DISEASE complications
- Publication
Digestive Diseases & Sciences, 2020, Vol 65, Issue 1, p189
- ISSN
0163-2116
- Publication type
journal article
- DOI
10.1007/s10620-019-05722-3