In patients with non-alcoholic fatty liver disease (NAFLD), insulin resistance (IR) associates with fibrosis progression independently of the hepatic inflammation, but the mechanisms are still unclear. We modeled the independent contribution of inflammation (non-alcoholic steatohepatitis: NASH) by exploiting the methionine-choline deficient (MCD) diet, and that of IR by insulin receptor (InsR) haploinsufficieny (InsR+/–) in the pathogenesis of liver fibrosis in C57BL/6 mice. We confirmed the study findings in 96 patients with NAFLD. InsR+/– enhanced hepatic fat content and impaired hepatic insulin signaling leading to Forkhead box protein O1 (FoxO1) accumulation in MCD-fed mice. Remarkably, despite reduced inflammation and hampered transdifferentiation of hepatic stellate cells (HSCs), InsR+/– promoted hepatic fibrosis accumulation, which correlated with the induction of the Lysyl Oxidase Like 2 (Loxl2), involved in matrix stabilization. Loxl2 up-regulation was not a cell autonomous property of insulin resistant HSCs, but was dependent on microparticles (MPs) released specifically by insulin resistant hepatocytes (HEPs) exposed to fatty acids. The mechanism entailed FoxO1 up-regulation, as FoxO1 silencing normalized Loxl2 expression reversing fibrosis in InsR+/– MCD-fed mice. Loxl2 up-regulation was similarly detected during IR induced by obesity, but not by lipogenic stimuli (fructose feeding). Most importantly, LOXL2 up-regulation was observed in NAFLD patients with type 2 diabetes (T2D) and LOXL2 hepatic and circulating levels correlated with histological fibrosis progression. IR favors fibrosis deposition independently of the classic ‘inflammation – HSC transdifferentiation’ pathway. The mechanism entails a cross-talk between enhanced lipotoxicity in insulin resistant HEPs and Loxl2 production by HSCs, which was confirmed in patients with diabetes, thereby facilitating extracellular matrix (ECM) stabilization.
Skip Nav Destination
Article navigation
June 2017
-
Cover Image
Cover Image
The accompanying caption is: Image demonstrates a 3D reconstruction of the neurovascular unit in a hippocampal artery in the mouse brain. For further details, see article by Nizari et al in this issue, pages 1207-1214. Image kindly provided by Cheryl Hawkes.
Research Article|
June 07 2017
Insulin resistance promotes Lysyl Oxidase Like 2 induction and fibrosis accumulation in non-alcoholic fatty liver disease
Paola Dongiovanni;
Paola Dongiovanni
*
1Internal Medicine, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milano, Milan, Italy
Correspondence: Paola Dongiovanni ([email protected]) or Luca Valenti ([email protected])
Search for other works by this author on:
Marica Meroni;
Marica Meroni
*
2Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
Search for other works by this author on:
Guido Alessandro Baselli;
Guido Alessandro Baselli
1Internal Medicine, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milano, Milan, Italy
Search for other works by this author on:
Giulia Alessandra Bassani;
Giulia Alessandra Bassani
3Department of Surgery, Center for Surgical Research, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milano, Milan, Italy
Search for other works by this author on:
Raffaela Rametta;
Raffaela Rametta
1Internal Medicine, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milano, Milan, Italy
Search for other works by this author on:
Alessandro Pietrelli;
Alessandro Pietrelli
1Internal Medicine, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milano, Milan, Italy
4Bioinformatic Group, Istituto Nazionale Genetica Molecolare (INGM), “Romeo ed Enrica Invernizzi”, Bioinformatic Group, Milan, Italy
Search for other works by this author on:
Marco Maggioni;
Marco Maggioni
5Pathology, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milano, Milan, Italy
Search for other works by this author on:
Federica Facciotti;
Federica Facciotti
6Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
Search for other works by this author on:
Valentina Trunzo;
Valentina Trunzo
7Flow Cytometry Service, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milan, Milan, Italy
Search for other works by this author on:
Sara Badiali;
Sara Badiali
8Surgery, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milano, Milan, Italy
Search for other works by this author on:
Silvia Fargion;
Silvia Fargion
1Internal Medicine, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milano, Milan, Italy
2Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
Search for other works by this author on:
Stefano Gatti;
Stefano Gatti
3Department of Surgery, Center for Surgical Research, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milano, Milan, Italy
Search for other works by this author on:
Luca Valenti
1Internal Medicine, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milano, Milan, Italy
2Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
Correspondence: Paola Dongiovanni ([email protected]) or Luca Valenti ([email protected])
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
February 26 2017
Revision Received:
April 10 2017
Accepted:
May 02 2017
Accepted Manuscript online:
May 02 2017
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2017
Clin Sci (Lond) (2017) 131 (12): 1301–1315.
Article history
Received:
February 26 2017
Revision Received:
April 10 2017
Accepted:
May 02 2017
Accepted Manuscript online:
May 02 2017
Citation
Paola Dongiovanni, Marica Meroni, Guido Alessandro Baselli, Giulia Alessandra Bassani, Raffaela Rametta, Alessandro Pietrelli, Marco Maggioni, Federica Facciotti, Valentina Trunzo, Sara Badiali, Silvia Fargion, Stefano Gatti, Luca Valenti; Insulin resistance promotes Lysyl Oxidase Like 2 induction and fibrosis accumulation in non-alcoholic fatty liver disease. Clin Sci (Lond) 1 June 2017; 131 (12): 1301–1315. doi: https://doi.org/10.1042/CS20170175
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
Open Access for all
We offer compliant routes for all authors from 2025. With library support, there will be no author nor reader charges in 5 journals. Check here |
![]() |