Leptin induces phagocytosis of apoptotic bodies by hepatic stellate cells via a rho guanosine triphosphatase-dependent mechanism

Joy X. Jiang, Kenichiro Mikami, Vijay Shah, Natalie J. Torok

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Abstract

Leptin, a profibrogenic cytokine, plays an important role in the development of non-alcoholic steatohepatitis. Leptin also regulates immune responses, including macrophage phagocytic activity. Stellate cells are key elements in liver fibrogenesis, and previously we have demonstrated that phagocytosis of apoptotic bodies by stellate cells is profibrogenic. To study the effects of leptin on the phagocytic activity of hepatic stellate cells, we exposed both LX-2 cells and primary stellate cells to leptin, and we have observed increased phagocytic activity. In stellate cells isolated from Zucker (fa/fa) rats, the rate of phagocytosis was significantly decreased. To investigate the mechanism by which leptin induces phagocytosis, we focused on the role of Rho-guanosine triphosphate (GTP)-ases. We found that leptin induced the PI3K-dependent activation of Rac1, and that nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase activation was also implicated in this process. Leptin also induced RhoA activation and translocation to the phagosomes. Expression of the constitutive active Rac1 and RhoA both increased the phagocytic rate, whereas inhibition of the Rho-dependent kinase decreased the phagocytic activity. Conclusion: We describe a novel role of leptin in the fibrogenic process, the induction of phagocytosis of apoptotic bodies by hepatic stellate cells. The data provide strong evidence of a Rho-GTPase-mediated regulation of the cytoskeleton during stellate cell phagocytosis. Leptin-mediated phagocytic activity of stellate cells therefore could be an important mechanism responsible for progression of fibrosis in non-alcoholic steatohepatitis.

Original languageEnglish (US)
Pages (from-to)1497-1505
Number of pages9
JournalHepatology
Volume48
Issue number5
DOIs
StatePublished - Nov 2008

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Hepatic Stellate Cells
Guanosine
Leptin
Phagocytosis
Fatty Liver
Extracellular Vesicles
Cytophagocytosis
rho-Associated Kinases
Phagosomes
rho GTP-Binding Proteins
Guanosine Triphosphate
Cytoskeleton
Phosphatidylinositol 3-Kinases
NADP
Oxidoreductases
Fibrosis
Macrophages
Cytokines

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

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Leptin induces phagocytosis of apoptotic bodies by hepatic stellate cells via a rho guanosine triphosphatase-dependent mechanism. / Jiang, Joy X.; Mikami, Kenichiro; Shah, Vijay; Torok, Natalie J.

In: Hepatology, Vol. 48, No. 5, 11.2008, p. 1497-1505.

Research output: Contribution to journalArticle

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