Role of Hepatic Lipoproteins in Transintestinal Cholesterol Efflux
Excess cholesterol is eliminated from the body by excretion in the feces. It is widely believed that the majority of fecal cholesterol is derived from bile secreted by the liver. However, there is mounting evidence that the liver may also create lipoproteins that can traffic excess cholesterol through the plasma to the small intestine. Through a process known as transintestinal cholesterol efflux (TICE), lipoprotein-associated cholesterol is internalized by the enterocytes and secreted into the lumen of the small intestine. The liver produces two different lipoproteins, high density lipoprotein (HDL) and very low density lipoprotein (VLDL), and based upon our and other groups’ data we hypothesize that VLDL or a by-product of VLDL such as LDL is responsible for funneling cholesterol into the TICE pathway. Our lab will be addressing this hypothesis by genetically manipulating the hepatic expression of genes involved HDL and VLDL production in wild type mice and NPC1L1 liver transgenic mice, which appear to excrete cholesterol primarily via TICE.
Effects of Anti-miR-33 on Atherosclerosis Regression and Reverse Cholesterol Transport
The risk of coronary heart disease (CHD), the largest major killer of Americans, is inversely associated with high-density lipoprotein cholesterol (HDL-C). The protective effects of HDL-C are believed to be due to the role of HDL in reverse cholesterol transport (RCT), a process whereby cholesterol from macrophage foam cells in atherosclerotic plaques is effluxed to HDL, transported to the liver, and excreted in the feces. Despite intense efforts to identify new therapeutic strategies to raise HDL, this has proven to be a challenging endeavor. A new and promising target for increasing HDL-C and RCT is microRNA-33 (miR-33). In humans, two isoforms of this microRNA, miR-33a and miR-33b, are encoded in introns of the sterol response element binding factor (SREBF) 2 and SREBF1 genes, and co-regulate cellular lipid homeostasis with their host genes. Notably, miR-33a/b induce mRNA degradation and/or translational repression of genes involved in cholesterol efflux and fatty acid oxidation. A major target of miR-33a/b is the ATP binding cassette transporter A1 (ABCA1), a protein essential for cholesterol efflux from foam cells and the formation of HDL. In mice, which encode only miR-33a, an antisense oligonucleotide targeting miR-33 (anti-miR-33) increased hepatic and macrophage ABCA1, HDL-C, RCT, and atherosclerosis regression. However the translational value of the studies in mice was limited by the lack of miR-33b, which is expressed in humans and non-humans primates. To test the effects of inhibiting both miR-33a and b, we recently treated African green monkeys with anti-miR- 33 and found that hepatic ABCA1 and HDL-C was elevated and very low-density lipoprotein (VLDL) triglyceride was decreased. While the preclinical findings to date highlight the cardioprotective potential of anti-miR-33, the ability of anti-miR-33 to induce the regression of atherosclerosis in a “human-like” species expressing both miR-33a and miR-33b is still unknown. Our lab proposes to determine the effects of anti-miR-33 on atherosclerosis regression and RCT in non-human primates. These studies will greatly aid in assessing anti-miR-33 as a potential clinical treatment for CHD.
Title: Effects of Anti-miR-33 on Atherosclerosis Regression and RCT in Nonhuman Primates
PI: Ryan E. Temel
Agency: NIH, NHLBI
Goal of Project: Determine whether miR-33 antagonism can stimulate atherosclerosis regression and reverse cholesterol transport in nonhuman primates.
Biliary sterol secretion is not required for macrophage reverse cholesterol transport. Temel RE, Sawyer JK, Yu L, Lord C, Degirolamo C, McDaniel A, Marshall S, Wang N, Shah R, Rudel LL, Brown JM. Cell Metab. 2010;12:96-102. PMCID: PMC2913877
Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Rayner KJ, Esau CC, Hussain FN, McDaniel AL, Marshall SM, van Gils JM, Ray TD, Sheedy FJ, Goedeke L, Liu X, Khatsenko OG, Kaimal V, Lees CJ, Fernandez-Hernando C, Fisher EA, Temel RE*, Moore KJ. Nature. 2011;478:404-7. PMCID: PMC3235584 (* co-contributing author)
Intestinal SR-BI Does Not Impact Cholesterol Absorption or Transintestinal Cholesterol Efflux (TICE) in Mice. Bura KS, Lord C, Marshall S, McDaniel A, Thomas G, Warrier M, Zhang J, Davis MA, Sawyer JK, Shah R, Wilson MD, Dikkers A, Tietge UJ, Collet X, Rudel LL, Temel RE*, Brown JM. J Lipid Res. 2013;54:1567-77. (* co-contributing author)