Abstract 17671: The Critical Role of Sterol Regulatory Element-binding Protein-1c in Hypertriglyceridemia Caused by Apolipoprotein A5 Deficiency

Introduction: The pivotal role of apolipoprotein A5 (apoA5) in hypertriglyceridemia (HTG) is evident from the fact that APOA5 deficiency predisposes to massive HTG (ca. 1,000 - 8,000 mg/dl) and that variants of APOA5 associate with the risk of HTG as well as cardiovascular diseases (CVDs). However, how HTG develops in the absence of apoA5 is not fully understood. Hypothesis: In human APOA5 deficiency, HTG is often predisposed by conditions associated with hyperinsulinemia such as diabetes, obesity and aging. Based on our previous findings that insulin activates sterol regulatory element-binding protein-1c (SREBP-1c) pathway, and that SREBP-1c plays a regulatory role in VLDL accumulation in a mouse model of HTG (Okazaki H et al. J Biol Chem 2010), we hypothesized that SREBP-1c plays an essential role in HTG of apoA5 deficiency. Methods: We took advantage of mice deficient in apoA5 ( Apoa5 -/- ), which develop only moderate HTG (ca. 500 mg/dl) on a chow diet at younger age, to identify factors that aggravate HTG. We then created mice deficient in both apoA5 and SREBP-1c ( Apoa5 -/- ;Srebp-1c -/- ) to test if SREBP-1c plays a dominant role in HTG of apoA5 deficiency. Results: We found that Apoa5 -/- develops age-dependent severe HTG, and the plasma levels of TG positively correlate with that of insulin. Deficiency of SREBP-1c almost completely rescued the age-related HTG in Apoa5 -/- . Pharmacological activation of SREBP-1c by LXR agonist (T0901317) via LXR-SREBP-1c pathway resulted in massive HTG in Apoa5 -/- (2,780 mg/dl) but not in Apoa5 -/- ;Srebp-1c -/- (200 mg/dl), supporting the essential role of SREBP-1c in HTG of apoA5 deficiency. We further found that T0901317 treatment increased the size of VLDL in Apoa5 -/- , but not in Apoa5 -/- ;Srebp-1c -/- . On the other hand, overexpression of apoA5 by recombinant adenovirus reduced plasma TG levels as well as decreased the number of large-sized VLDL particles. Conclusions: These results suggest that apoA5 is necessary for the catabolism of large-sized VLDL particles, and the activation of SREBP-1c aggravates HTG of apoA5 deficiency by increasing the production of large-sized VLDL particles.