Abstract 68: Reducing Hepatic Very-Low-Density Lipoprotein Production by Knockdown of Microsomal Triglyceride Transfer Protein Decreases Transintestinal Cholesterol Excretion

Atherosclerotic coronary vascular disease (ASCVD) remains the number one killer of Americans. A way to reduce the low-density lipoprotein cholesterol (LDLc), the primary risk factor of ASCVD, is to increase cholesterol excretion from the body. Our group and others have recently found that cholesterol excretion can be facilitated by both biliary and non-biliary pathways. The lipoprotein that delivers cholesterol from the liver through the plasma to the small intestine (SI) for transintestinal cholesterol excretion (TICE) is not yet known. We hypothesized that cholesterol leaves the liver via very low-density lipoproteins (VLDL) for TICE. We assessed this hypothesis by using antisense oligonucleotides (ASO) to knockdown hepatic expression of microsomal triglyceride transfer protein (MTP), which is necessary for VLDL assembly. While maintained on a high cholesterol (0.2% wt/wt) diet for six weeks, wild type (WT) mice and hepatic Niemann-Pick C1-like 1 transgenic mice (L1Tg), which predominantly excrete cholesterol via TICE, were treated with control ASO or MTP ASO. In both WT and L1Tg mice, MTP ASO decreased hepatic MTP protein expression by 60% and increased hepatic total cholesterol concentration 3.5 fold. Regardless of treatment with control or MTP ASO, L1Tg mice had an 80% reduction in biliary cholesterol compared to WT mice. However, L1Tg mice treated with MTP ASO displayed a 60% reduction in fecal neutral sterol (FNS) excretion. In summary our data show that when VLDL production is decreased in mice with reduced biliary cholesterol secretion capacity, FNS excretion is impaired. These data support our conclusion that cholesterol leaves the liver through VLDL for TICE.