RGD Reference Report - Insulin resistance promotes Lysyl Oxidase Like 2 induction and fibrosis accumulation in non-alcoholic fatty liver disease. - Rat Genome Database

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

Authors: 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 
Citation: Dongiovanni P, etal., Clin Sci (Lond). 2017 Jun 7;131(12):1301-1315. doi: 10.1042/CS20170175. Print 2017 Jun 1.
RGD ID: 14700929
Pubmed: PMID:28468951   (View Abstract at PubMed)
DOI: DOI:10.1042/CS20170175   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
INSRHumanmetabolic dysfunction-associated steatotic liver disease susceptibilityISOInsr (Mus musculus)DNA:deletion:cds: (codon 306 and exon 4) (mouse)RGD 
INSRHumanmetabolic dysfunction-associated steatotic liver disease susceptibilityISOInsr (Rattus norvegicus)DNA:deletion:cds:codon 306 in exon 4 (mouse)RGD 
InsrRatmetabolic dysfunction-associated steatotic liver disease susceptibilityISOInsr (Mus musculus)DNA:deletion:cds: (codon 306 and exon 4) (mouse)RGD 
InsrRatmetabolic dysfunction-associated steatotic liver disease susceptibilityIMP DNA:deletion:cds:codon 306 in exon 4 (mouse)RGD 
InsrMousemetabolic dysfunction-associated steatotic liver disease susceptibilityISOInsr (Rattus norvegicus)DNA:deletion:cds:codon 306 in exon 4 (mouse)RGD 
InsrMousemetabolic dysfunction-associated steatotic liver disease susceptibilityIMP DNA:deletion:cds: (codon 306 and exon 4) (mouse)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Insr  (insulin receptor)

Genes (Mus musculus)
Insr  (insulin receptor)

Genes (Homo sapiens)
INSR  (insulin receptor)


Additional Information