Universität zu Köln

Mittenbuehler, Melanie J., Sprenger, Hans-Georg, Gruber, Sabine, Wunderlich, Claudia M., Kern, Lara, Bruening, Jens C. and Wunderlich, F. Thomas (2018). Hepatic leptin receptor expression can partially compensate for IL-6R alpha deficiency in DEN-induced hepatocellular carcinoma. Mol. Metab., 17. S. 122 - 134. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 2212-8778

Full text not available from this repository.

Abstract

Objective: The current obesity pandemic represents a major health burden, given that it predisposes to the development of numerous obesity-associated disorders. The obesity-derived adipokines not only impair systemic insulin action but also increase the incidence of hepatocellular carcinoma (HCC), a highly prevalent cancer with poor prognosis. Thus, worldwide incidences of HCC are expected to further increase, and defining the molecular as well as cellular mechanisms will allow for establishing new potential treatment options. The adipose tissue of obese individuals increases circulating leptin and interleukin-6 (IL-6) levels, which both share similar signaling capacities such as Signal Transducer and Activator of Transcription 3 (STAT3) and Phosphoinositide 3-kinase (PI3K)/Akt activation. While mouse models with deficient IL-6 signaling show an ameliorated but not absent Diethylnitrosamine (DEN)-induced HCC development, the morbid obesity in mice with mutant leptin signaling complicates the dissection of hepatic leptin receptor (LEPR) and IL-6 signaling in HCC development. Here we have investigated the function of compensating hepatic LEPR expression in HCC development of IL-6R alpha-deficient mice. Methods: We generated and characterized a mouse model of hepatic LEPR deficiency that was intercrossed with IL-6R alpha-deficient mice. Cohorts of single and double knockout mice were subjected to the DEN-HCC model to ascertain liver cancer development and characterize metabolic alterations. Results: We demonstrate that both high-fat diet (HFD)-induced obesity and IL-6R alpha deficiency induce hepatic Lepr expression. Consistently, double knockout mice show a further reduction in tumor burden in DEN-induced HCC when compared to control and single LepR(L-KO)/IL-6R alpha knock out mice, whereas metabolism remained largely unaltered between the genotypes. Conclusions: Our findings reveal a compensatory role for hepatic LEPR in HCC development of IL-6Ra-deficient mice and suggest hepatocyte-specific leptin signaling as promoter of HCC under obese conditions. (C) 2018 The Authors. Published by Elsevier GmbH.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mittenbuehler, Melanie J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sprenger, Hans-Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Gruber, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Wunderlich, Claudia M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kern, Lara UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruening, Jens C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wunderlich, F. Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-168463
DOI:	10.1016/j.molmet.2018.08.010
Journal or Publication Title:	Mol. Metab.
Volume:	17
Page Range:	S. 122 - 134
Date:	2018
Publisher:	ELSEVIER SCIENCE BV
Place of Publication:	AMSTERDAM
ISSN:	2212-8778
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SUBCUTANEOUS ADIPOSE-TISSUE; NECROSIS-FACTOR-ALPHA; INSULIN-RESISTANCE; INTERLEUKIN-6 RECEPTOR; LIVER-CANCER; IN-VIVO; CHEMICAL HEPATOCARCINOGENESIS; NONALCOHOLIC STEATOHEPATITIS; STAT3 ACTIVATION; PROSTATE-CANCER Multiple languages Endocrinology & Metabolism Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16846