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

Abstract

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) haploinsufficiency (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.

• Authors: 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
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 131 Issue 12 Pg. 1301-1315 (06 01 2017) ISSN: 1470-8736 [Electronic] England
• PMID: 28468951 (Publication Type: Journal Article)
• Copyright: © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• Forkhead Box Protein O1
• Foxo1 protein, mouse
• Methionine
• Amino Acid Oxidoreductases
• LOXL2 protein, human
• Loxl2 protein, mouse
• Receptor, Insulin

Topics

• Amino Acid Oxidoreductases (biosynthesis)
• Animals
• Cell Proliferation
• Cell Transdifferentiation
• Cells, Cultured
• Choline Deficiency (complications)
• Diabetes Mellitus, Type 2 (enzymology, pathology)
• Disease Models, Animal
• Enzyme Induction
• Extracellular Matrix (metabolism)
• Forkhead Box Protein O1 (genetics, metabolism)
• Genetic Predisposition to Disease
• Hepatic Stellate Cells (enzymology, pathology)
• Hepatocytes (enzymology, pathology)
• Humans
• Insulin Resistance
• Liver (enzymology, pathology)
• Liver Cirrhosis (enzymology, etiology, genetics, pathology)
• Methionine (deficiency)
• Mice, Inbred C57BL
• Mice, Knockout
• Non-alcoholic Fatty Liver Disease (enzymology, etiology, genetics, pathology)
• Phenotype
• Receptor, Insulin (deficiency, genetics)
• Signal Transduction