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Targeting hepatic kisspeptin receptor ameliorates non-alcoholic fatty liver disease in a mouse model.

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Title: Targeting hepatic kisspeptin receptor ameliorates non-alcoholic fatty liver disease in a mouse model.
Authors: Guzman, S
Dragan, M
Kwon, H
De Oliveira, V
Rao, S
Bhatt, V
Kalemba, KM
Shah, A
Rustgi, VK
Wang, H
Bech, PR
Abbara, A
Izzi-Engbeaya, C
Manousou, P
Guo, JY
Guo, GL
Radovick, S
Dhillo, WS
Wondisford, FE
Babwah, AV
Bhattacharya, M
Item Type: Journal Article
Abstract: Nonalcoholic fatty liver disease (NAFLD), the most common liver disease has become a silent worldwide pandemic. The incidence of NAFLD correlates with the rise in obesity, type 2 diabetes and metabolic syndrome. A hallmark feature of NAFLD is excessive hepatic fat accumulation or steatosis, due to dysregulated hepatic fat metabolism which can progress to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Currently, there are no approved pharmacotherapies to treat this disease. Here we have identified that activation of the kisspeptin receptor (KISS1R) signaling pathway has therapeutic effects in NAFLD. Using high fat diet-fed mice, we demonstrated that a deletion of hepatic Kiss1r exacerbated hepatic steatosis. In contrast, enhanced stimulation of KISS1R protected against steatosis in wild-type C57BL/6J mice and decreased fibrosis using a diet-induced mouse model of NASH. Mechanistically, we found that hepatic KISS1R signaling activates the master energy regulator, AMPK, to thereby decrease lipogenesis and progression to NASH. In NAFLD patients and in HFD-fed mice, hepatic KISS1/KISS1R expression and plasma kisspeptin levels were elevated, suggesting a compensatory mechanism to reduce triglyceride synthesis. These findings establish KISS1R as a therapeutic target to treat NASH.
Issue Date: 16-May-2022
Date of Acceptance: 23-Mar-2022
URI: http://hdl.handle.net/10044/1/96362
DOI: 10.1172/JCI145889
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation
Start Page: 1
End Page: 20
Journal / Book Title: Journal of Clinical Investigation
Volume: 132
Issue: 10
Copyright Statement: Copyright © 2022, Guzman et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: CS-2018-18-ST2-002
Keywords: G protein–coupled receptors
Mouse models
Diabetes Mellitus, Type 2
Diet, High-Fat
Disease Models, Animal
Liver Cirrhosis
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease
Receptors, Kisspeptin-1
G proteincoupled receptors
Mouse models
11 Medical and Health Sciences
Publication Status: Published
Conference Place: United States
Open Access location: https://www.jci.org/articles/view/145889
Online Publication Date: 2022-05-16
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Faculty of Medicine

This item is licensed under a Creative Commons License Creative Commons