{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:57:39Z","timestamp":1791557859322,"version":"4.3.4"},"reference-count":46,"publisher":"Portland Press Ltd.","issue":"12","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,6,1]]},"abstract":"<jats:p>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+\/\u2013) in the pathogenesis of liver fibrosis in C57BL\/6 mice. We confirmed the study findings in 96 patients with NAFLD. InsR+\/\u2013 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+\/\u2013 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+\/\u2013 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 \u2018inflammation \u2013 HSC transdifferentiation\u2019 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.<\/jats:p>","DOI":"10.1042\/cs20170175","type":"journal-article","created":{"date-parts":[[2017,5,4]],"date-time":"2017-05-04T00:25:40Z","timestamp":1493857540000},"page":"1301-1315","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Insulin resistance promotes Lysyl Oxidase Like 2 induction and fibrosis accumulation in non-alcoholic fatty liver disease"],"prefix":"10.1042","volume":"131","author":[{"given":"Paola","family":"Dongiovanni","sequence":"first","affiliation":[{"name":"Internal Medicine, Fondazione IRCCS Ca\u2019 Granda Ospedale Policlinico Milano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marica","family":"Meroni","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido\u00a0Alessandro","family":"Baselli","sequence":"additional","affiliation":[{"name":"Internal Medicine, Fondazione IRCCS Ca\u2019 Granda Ospedale Policlinico Milano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia\u00a0Alessandra","family":"Bassani","sequence":"additional","affiliation":[{"name":"Department of Surgery, Center for Surgical Research, Fondazione IRCCS Ca\u2019 Granda Ospedale Policlinico Milano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaela","family":"Rametta","sequence":"additional","affiliation":[{"name":"Internal Medicine, Fondazione IRCCS Ca\u2019 Granda Ospedale Policlinico Milano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Pietrelli","sequence":"additional","affiliation":[{"name":"Internal Medicine, Fondazione IRCCS Ca\u2019 Granda Ospedale Policlinico Milano, Milan, Italy"},{"name":"Bioinformatic Group, Istituto Nazionale Genetica Molecolare (INGM), \u201cRomeo ed Enrica Invernizzi\u201d, Bioinformatic Group, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Maggioni","sequence":"additional","affiliation":[{"name":"Pathology, Fondazione IRCCS Ca\u2019 Granda Ospedale Policlinico Milano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Facciotti","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, European Institute of Oncology, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Trunzo","sequence":"additional","affiliation":[{"name":"Flow Cytometry Service, Fondazione IRCCS Ca\u2019 Granda Ospedale Policlinico Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Badiali","sequence":"additional","affiliation":[{"name":"Surgery, Fondazione IRCCS Ca\u2019 Granda Ospedale Policlinico Milano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Fargion","sequence":"additional","affiliation":[{"name":"Internal Medicine, Fondazione IRCCS Ca\u2019 Granda Ospedale Policlinico Milano, Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Gatti","sequence":"additional","affiliation":[{"name":"Department of Surgery, Center for Surgical Research, Fondazione IRCCS Ca\u2019 Granda Ospedale Policlinico Milano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Valenti","sequence":"additional","affiliation":[{"name":"Internal Medicine, Fondazione IRCCS Ca\u2019 Granda Ospedale Policlinico Milano, Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2017,6,7]]},"reference":[{"key":"2021113011015877400_B1","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1001\/jama.2015.5370","article-title":"Nonalcoholic fatty liver disease: a systematic review","volume":"313","author":"Rinella","year":"2015","journal-title":"JAMA"},{"key":"2021113011015877400_B2","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.dld.2015.10.027","article-title":"A \u201csystems medicine\u201d approach to the study of non-alcoholic fatty liver disease","volume":"48","author":"Petta","year":"2016","journal-title":"Dig. 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