Abstract 21171: Combinatorial Aso-Mediated Knockdown of ApoB and DGAT2 Inhibits Both VLDL Secretion and High Fat Diet Induced Hepatic Steatosis

We previously demonstrated that mice fed a Western-type and treated with apoB antisense (ASO) for 6 weeks had both reductions in VLDL secretion and the same levels of hepatic triglycerides (TG) as did mice receiving control ASO. The reduction in hepatic TG was due to trapping of TG that had been transferred to the ER lumen by MTP where it was trapped because of the knockdown (KD) of apoB. Trapped ER-TG stimulated endoplasmic reticulum (ER) autophagy (A), which transported ER-TG to lysosomes where it was hydrolyzed to fatty acids (FA) that were oxidized by mitochondria. We have used this model in test if ASO treatment to KD apoB together with either diacylglycerol-acylt-transferase-1 (DGAT1) or DGAT2 ASO-KD would (1) reduce hepatic TG to levels below mice receiving only control ASO, and (2) provide insights into whether either DGAT1 or DGAT2 preferentially transferred newly synthesized TG into the ER. ASO-KD of either DGAT1 or DGAT2 alone reduced secretion of apoB and TG about 30-40%, but hepatic TG was mu...