Leptin Enhances Hepatic Fibrosis and Inflammation in a Mouse Model of Cholestasis

Anca D. Petrescu, Stephanie Grant, Elaina Williams, Su Yeon An, Nikhil Seth, Mark Shell, Tyson Amundsen, Christopher Tan, Yusra Nadeem, Matthew Tjahja, Lancaster Weld, Christopher S. Chu, Julie Venter, Gabriel Frampton, Matthew McMillin, Sharon DeMorrow

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Leptin is an adipokine with roles in food intake and energy metabolism through its actions on neurons in the hypothalamus. The role of leptin in obesity and cardiovascular disorders is well documented. However, its influence on liver conditions such as cholestasis is poorly understood. The effects of exogenous leptin and leptin-neutralizing antibody on biliary hyperplasia, hepatic fibrosis, and inflammation in the multidrug resistance protein 2 knockout (Mdr2KO) mouse model of cholestasis were assessed by quantifying markers specific for cholangiocytes, activated hepatic stellate cells (HSCs), and cytokines. Serum and hepatic leptin were increased in Mdr2KO mice compared with FVB/NJ (FVBN) controls, and exogenous leptin enhanced biliary hyperplasia and liver fibrosis in Mdr2KO and FVBN mice. Leptin administration increased hepatic expression of C-C motif chemokine ligand 2 and IL-6 in Mdr2KO mice. In contrast, leptin-neutralizing antibody reduced intrahepatic bile duct mass and decreased HSC activation in Mdr2KO mice compared with FVBN controls. Sex-related differences were noted, with female Mdr2KO mice having more leptin than males. In cholangiocytes and LX2 cells in vitro, leptin increased phosphorylated Akt and stimulated cell proliferation. Leptin receptor siRNA and inhibitors of Akt phosphorylation impaired leptin-induced cell proliferation and proinflammatory cytokines. The current data suggest that leptin is abnormally increased in cholestatic mice, and excess leptin increases ductular reaction, hepatic fibrosis, and inflammation via leptin receptor–mediated phosphorylation of Akt in cholangiocytes and HSCs.

Original languageEnglish (US)
Pages (from-to)484-502
Number of pages19
JournalAmerican Journal of Pathology
Volume192
Issue number3
DOIs
StatePublished - Mar 2022

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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