Endocrine Abstracts

Background: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of progressive liver diseases driven in part by macrophages, occurring in the absence of excessive alcohol consumption that ranges from simple steatosis to non-alcoholic steato-hepatitis (NASH), ultimately progressing to fibrosis/cirrhosis and hepatocellular carcinoma. NAFLD is associated with insulin resistance and confers an increased risk of cardiovascular disease. Pre-menopausal women are protected against NAFLD, which has been provisionally attributed to oestrogen levels and/or differences in sex hormone receptor expression levels in immune cells, but definitive mechanisms are unclear. SHIP2 is a 5’ lipid phosphatase which acts as a negative regulator of the PI3K arm of insulin signalling. SHIP2 is expressed in insulin sensitive mouse and human cells including macrophages. Mouse studies overexpressing SHIP2 or knocking out SHIP2 show dramatic effects impacting insulin sensitivity and protection from obesity.

Methods: To explore the impact of macrophage specific-insulin resistance on NAFLD progression we generated a novel mouse model of macrophage-specific SHIP2 catalytic activity knockdown (M-SHIP2 ^KD).

Results: The M-SHIP2 ^KD model is viable, fertile, and exhibits normal development. Bone marrow derived macrophages (BMDM) from M-SHIP2 ^KD display expression of the catalytically inactive SHIP2 mRNA and altered response to insulin. Despite no high-fat high-cholesterol diet challenge, 12 month old male mice reveal increase in abundance and size of lipid droplets in their livers compared to controls. Female M-SHIP2KD mice at 12 months of age do not exhibit fatty livers compared to controls. Ongoing transcriptomics analyses from liver samples are revealing multiple significant differentially regulated genes in male vs female livers.

Conclusion: Macrophage-specific insulin resistance through SHIP2 knockdown in aged mice without diet challenge results in lipid droplet accumulation in the livers of male mice only, females are protected, which may be reflective of the protective effects that premenopausal females exhibit in the clinical situation.