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

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          Abstract

          Background & Aims: In patients with nonalcoholic fatty liver disease (NAFLD), insulin resistance (IR) associates with fibrosis progression independently of hepatic inflammation, but the mechanisms are still unclear. Methods : We modeled the independent contribution of inflammation (steatohepatitis: NASH) by exploiting the methionine-choline deficient (MCD) diet, and that of IR by insulin receptor haploinsufficiency (InsR+/-), in the pathogenesis of liver fibrosis in C57Bl/6 mice. We confirmed study findings in 96 patients with NAFLD. Results: 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 trans-differentiation of hepatic stellate cells (HSCs), InsR+/- promoted hepatic fibrosis accumulation, which correlated with induction of the Lysyl-oxidase like-2 (Loxl2), involved in matrix stabilization. Loxl2 upregulation was not a cell-autonomous property of insulin resistant HSCs, but was dependent on microparticles released specifically by insulin resistant hepatocytes exposed to fatty acids. The mechanism entailed FoxO1 upregulation, as FoxO1 silencing normalized Loxl2 expression reversing fibrosis in InsR+/-MCD-fed mice. Loxl2 upregulation was similarly detected during IR induced by obesity, but not by lipogenic stimuli (fructose feeding). Most importantly, LOXL2 upregulation was observed in NAFLD patients with type 2 diabetes, and LOXL2 hepatic and circulating levels correlated with histological fibrosis progression. Conclusions: IR favors fibrosis deposition independently of the classic "inflammation - HSC trans-differentiation" pathway. The mechanism entails a cross-talk between enhanced lipotoxicity in insulin resistant hepatocytes and Loxl2 production by HSCs, which was confirmed in patients with diabetes, thereby facilitating extracellular matrix stabilization.

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          Author and article information

          Journal
          Clin. Sci.
          Clinical science (London, England : 1979)
          Portland Press Ltd.
          1470-8736
          0143-5221
          May 03 2017
          Affiliations
          [1 ] Internal Medicine, Fondazione IRCCS Cà Granda, Ospedale Policlinico Milano, Via Francesco Sforza 35, Milano, Italy.
          [2 ] Department of Pathophysiology and Transplantation, Università degli Studi Milano, Fondazione IRCCS Ca' Granda, Pad Granelli via F Sforza 35, Milano, 20122, Italy.
          [3 ] Center for Surgical Research, Fondazione IRCCS Cà Granda, Ospedale Policlinico Milano, Milano, Italy.
          [4 ] Internal Medicine, Fondazione IRCCS Cà Granda, Osepdale Policlinico Milano, Via Francesco Sforza 35, Milano, Italy.
          [5 ] Bioinformatic Group, Istituto Nazionale Genetica Molecolare (INGM), "Romeo ed Enrica Invernizzi, Via Francesco Sforza 35, Milano, Italy.
          [6 ] Pathology, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico Milano, Via Francesco Sforza 35, Milano, Italy.
          [7 ] Department of Experimental Oncology, European Institute of Oncology, Milano, Italy.
          [8 ] Flow Cytometry Service, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Via Francesco Sforza 35, Milano, Italy.
          [9 ] Surgery, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Via Francesco Sforza 35, Milano, Italy.
          [10 ] University of Milan, Milan, United States.
          [11 ] Center for Surgical Research Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milano, Via Francesco Sforza 35, Milano, Italy.
          [12 ] Department of Pathophysiology and Transplantation, Università degli Studi Milano, Fondazione IRCCS Ca' Granda, Pad Granelli via F Sforza 35, Milano, 20122, Italy luca.valenti@unimi.it.
          Article
          CS20170175
          10.1042/CS20170175
          28468951
          9bc7d887-d00b-4c3f-8c5a-e5688d51ab6b
          History

          Experimental model,FoxO1,Nash,diabetes,extracellular matrix
          Experimental model, FoxO1, Nash, diabetes, extracellular matrix

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