Insulin resistance promotes Lysyl Oxidase Like 2 induction and fibrosis accumulation in non-alcoholic fatty liver disease

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

Research output: Contribution to journalArticle

Abstract

In patients with non-alcoholic fatty liver disease (NAFLD), insulin resistance (IR) associates with fibrosis progression independent 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) haploinsufficient mice (InsR+/-), in the pathogenesis of liver fibrosis in C57BL/6mice.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 inMCD-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 independent 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.

Original languageEnglish
Pages (from-to)1301-1315
Number of pages15
JournalClinical Science
Volume131
Issue number12
DOIs
Publication statusPublished - Jun 1 2017

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Protein-Lysine 6-Oxidase
Insulin Receptor
Hepatic Stellate Cells
Insulin Resistance
Fibrosis
Up-Regulation
Liver
Insulin
Inflammation
Choline
Methionine
Hepatocytes
Cell Transdifferentiation
Disease Resistance
Fatty Liver
Fructose
Liver Cirrhosis
Type 2 Diabetes Mellitus
Extracellular Matrix
Fatty Acids

ASJC Scopus subject areas

  • Medicine(all)

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Insulin resistance promotes Lysyl Oxidase Like 2 induction and fibrosis accumulation in non-alcoholic fatty liver disease. / Dongiovanni, Paola; Meroni, Marica; Baselli, Guido Alessandro; Bassani, Giulia Alessandra; Rametta, Raffaela; Pietrelli, Alessandro; Maggioni, Marco; Facciotti, Federica; Trunzo, Valentina; Badiali, Sara; Fargion, Silvia; Gatti, Stefano; Valenti, Luca.

In: Clinical Science, Vol. 131, No. 12, 01.06.2017, p. 1301-1315.

Research output: Contribution to journalArticle

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AU - Meroni, Marica

AU - Baselli, Guido Alessandro

AU - Bassani, Giulia Alessandra

AU - Rametta, Raffaela

AU - Pietrelli, Alessandro

AU - Maggioni, Marco

AU - Facciotti, Federica

AU - Trunzo, Valentina

AU - Badiali, Sara

AU - Fargion, Silvia

AU - Gatti, Stefano

AU - Valenti, Luca

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