Hepatosteatosis is strongly associated with hyperinsulinaemia and obesity. Previously, we demonstrated accelerated atherosclerosis and impaired glucose tolerance in L-PGDS knockout (KO) mice. Interestingly, L-PGDS KO mice also exhibit hyperinsulinemia on high fat diet in a time-dependent manner. In this study, we investigated the role of L-PGDS on liver pathophysiology using L-PGDS KO mice compared to control C57BL/6 mice) (n=6/group). Mice were kept on high fat diet (60% fat) for 14 weeks and all parameters were measured initially and at 4-, 8- and 14-weeks post high fat diet. Data were analyzed by unpaired t-test or one-way ANOVA where appropriate with p<0.05 deemed significant. Fasting insulin, blood glucose and calculated HOMA-IR were determined. KO mice showed significantly higher HOMA-RI 19.3± 4.62 and 19.7±4.74 at 8 and 14 weeks, respectively, compared to the C57BL/6 mice, which were 7.73±1.14 and 10.1±1.87 at 8 and 14 weeks, respectively. Hepatic Cd36 protein expression was significantly increased at 14 weeks in KO mice compared to the control. Liver steatosis directly correlated with elevated serum triglyceride levels, which significantly increased to 81.7±3.24 and 82.8±1.63 mg/dl at 8 and 14 week,s respectively, compared to the initial level of 64.1±5.66 mg/dl Control serum triglyceride levels were 61.1±3.49 and 73.6±3.2 mg/dl at 8 and 14 weeks, respectively. Furthermore, immunohistochemistry staining of lipid showed severely more liver steatosis in KO mice at all-time points when compared to control mice. Interestingly, KO mice always weighed less compared to the control mice at all-time points, which suggests that L-PGDS partially or fully contributes towards the development of hepatosteatosis independent of body weight. We conclude that L-PGDS is an essential component of hepatic metabolic substrate utilization and may play a significant role in diabetes-related steatosis.


S. Kumar: None. T. Palaia: None. C. Hall: None. J. Lee: None. M. Stevenson: None. L. Ragolia: None.

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