Abstract 19406: Amelioration of Streptozotocin-Induced Diabetic Hypertriglyceridemia in the Absence of Hormone-Sensitive Lipase
Background: The molecular mechanism of diabetic lipemia in the setting of insulin deficiency is not fully understood. We unexpectedly found the role of hormone-sensitive lipase (HSL) in diabetic lipemia --- the plasma level of triglycerides is lower in HSL deficient mice (Hsl-/-) than in wild-type mice (WT) when they are challenged with streptozotocin (STZ).
Aim/Hypothesis: The current study was undertaken to elucidate the molecular mechanism by which diabetic lipemia in insulin deficiency is ameliorated in Hsl-/-. We hypothesized that HSL would be necessary either in VLDL production, chylomicron (CM) production, or VLDL/CM clearance.
Methods: WT and Hsl-/- male littermates at 10-13 weeks old were injected with 100 mg/body weight (kg) of STZ twice every other day using a standard protocol. Plasma levels of triglycerides were measured after challenging these mice with 1) fat-free high sucrose diet to stimulate VLDL production, 2) olive oil gavage to increase CM production, and/or 3) Triton WR-1339 to block VLDL/CM clearance. The mRNA levels of lipoprotein lipase (LPL) and LPL-related genes (Angptl3, Angptl4, Gpihbp1, Lmf1, etc.) in various tissues (white adipose tissue, liver, and muscle) were evaluated by quantitative polymerase chain reaction. Plasma LPL activity was measured using 3H-triolein in post-heparin plasma obtained from WT or Hsl-/-.
Results: WT and Hsl-/- equally became diabetic and insulin-deficient by STZ treatment. In WT, the plasma level of triglycerides was not increased after feeding fat-free diet, but increased dramatically after olive oil gavage, implicating the dominant contribution of CM accumulation, but not VLDL accumulation, in STZ-induced hypertriglyceridemia. Compared to WT, the increase in plasma triglycerides after olive oil gavage is substantially lowered in Hsl-/- both in the presence and absence of Triton WR-1339, suggesting that HSL deficiency reduces at least partially CM production. Measurement of plasma LPL activity and mRNA levels of LPL and other LPL related genes did not reveal any difference between WT and Hsl-/- in the insulin-deficient status.
Conclusions: HSL deficiency ameliorates STZ-induced diabetic hypertriglyceridemia at least partially by reducing CM production.
Author Disclosures: M. Takanashi: None. S. Takase: None. Y. Taira: None. T. Kimura: None. S. Okazaki: None. P. Xu: None. C. Li: None. F. Shionoiri: None. Y. Iizuka: None. J. Osuga: None. S. Ishibashi: None. T. Kadowaki: None. H. Okazaki: None.
- © 2016 by American Heart Association, Inc.