Cholesterol homeostasis alters one carbon metabolism in vitro and in vivo

Abstract

Cholesterol essential for the synthesis of steroid hormones, bile acids, and lipoproteins. Hyperhomocysteinemia and hypercholesterolemia are both risk factors for human cardiovascular diseases. Previous studies reported that cholesterol biosynthesis can be regulated by homocysteine‐induced endoplasmic reticulum stress in primary human umbilical vein endothelial cells (HUVEC), hepatocellular carcinoma cell line (HepG2), and in murine models. However, the physiological impact of excessive cholesterol exposure on one‐carbon metabolism is unknown. We hypothesize that cholesterol may alter methionine adenosyltransferase 1A (MAT1a) expression via sterol regulatory element‐binding proteins (SREBPs) that have been shown to target the promoter of MAT1a gene. Physiological doses of cholesterol or mevastatin, an inhibitor of cholesterol synthesis, were used to alter cellular cholesterol contents in liver derived cell lines L02. Mice fed high cholesterol diets or cholesterol‐lowering drugs were used as in vivo models. We discovered that ratios of nuclear/ total SREBPs tended were altered by cholesterol and mevestatin treatments in the cell models. Furthermore, reporter assay demonstrated that cholesterol treatment but not mevastatin significantly increased MAT1a promoter activity, supporting our hypothesis. Preliminary data from stable isotopic tracer experiments also showed consistent results that cholesterol alters MAT expression and S‐adenosyl‐ methionine synthesis in vitro. We demonstrated novel findings on how cholesterol homeostasis interacts with methyl group kinetics in mammalian cells. The in vivo kinetics studies on how cholesterol affect one carbon metabolism are underway.Support or Funding InformationMOST 104‐2320‐B005‐010‐MY3; MOST104‐2911‐I005‐301; Ministry of Education, Taiwan, R.O.C. under the ATU plan