The Effects of Choline on Hepatic Lipid Metabolism, Mitochondrial Function and Antioxidative Status in Human Hepatic C3A Cells Exposed to Excessive Energy Substrates

Abstract

Choline plays a lipotropic role in lipid metabolism as an essential nutrient. In this study, we investigated the effects of choline (5, 35 and 70 μM) on DNA methylation modifications, mRNA expression of the critical genes and their enzyme activities involved in hepatic lipid metabolism, mitochondrial membrane potential (Δψm) and glutathione peroxidase (GSH-Px) in C3A cells exposed to excessive energy substrates (lactate, 10 mM; octanoate, 2 mM and pyruvate, 1 mM; lactate, octanoate and pyruvate-supplemented medium (LOP)). Thirty five micromole or 70 μM choline alone, instead of a low dose (5 μM), reduced hepatocellular triglyceride (TG) accumulation, protected Δψm from decrement and increased GSH-Px activity in C3A cells. The increment of TG accumulation, reactive oxygen species (ROS) production and Δψm disruption were observed under LOP treatment in C3A cells after 72 h of culture, which were counteracted by concomitant treatment of choline (35 μM or 70 μM) partially via reversing the methylation status of the peroxisomal proliferator-activated receptor alpha (PPARα) gene promoter, upregulating PPARα, carnitine palmitoyl transferase-I (CPT-I) and downregulating fatty acid synthase (FAS) gene expression, as well as decreasing FAS activity and increasing CPT-I and GSH-Px activities. These findings provided a novel insight into the lipotropic role of choline as a vital methyl-donor in the intervention of chronic metabolic diseases.

Metabolomic profiling reveals differential effects of glucagon‐like peptide‐1 and insulin on nutrient partitioning in ovine liver

“…These results probably indicate that the enhanced lipogenesis was not associated with simultaneous increase in cholesterol metabolism for lipoprotein package and export out of the liver and consequently greater infiltration of triglyceride in the liver (Zhu et al . ). This action may relate to a pathophysiological situation induced by a higher concentration of insulin or, alternatively, may imply an insulin‐independent role for GLP‐1 in regulation of lipid metabolism.…”

Fatty acid-induced lipotoxicity inhibits choline metabolism independent of ER stress in mouse primary hepatocytes

“…It is well known that altering choline availability or hepatic choline metabolism drives patterns of altered lipid homeostasis (10,(28)(29)(30)(31)(32)(33)(34)(35). Early studies by Charles Best and others documented that liver dysfunction associated with choline deficiency was reversed by choline supplementation via delivery of PC (4)(5)(6).…”

Peroxisome Proliferator-Activated Receptor α in Lipid Metabolism and Atherosclerosis

“…In direct opposition of NPC1L1, the ABCG5/ABCG8 heterodimer limits intestinal absorption and facilitates biliary secretion of cholesterol [2]. Mutations in SOD, GSH-Px, CAT Upregulation [50][51][52] VLDL metabolism MTP Upregulation [53] either ABCG5 or ABCG8 cause sitosterolemia. Treatment of Hep3B cells with pravastatin results in a significant increase in ABCG5 and ABCG8 levels, at least partially, by activating PPARα/liver X receptor α (LXRα) signaling pathway [25].…”

“…It was reported that PPARα activation suppresses the expression of nicotinamide dinucleotide phosphate oxidase 4 (NOX4) and then attenuates superoxide production in the rat aorta [49]. On the other hand, treatment with PPARα ligands elevates the activities of endogenous antioxidase including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) to remove free radicals [50][51][52]. Thus, a decrease in NOX4 expression as well as an increase in SOD, GSH-Px, and CAT activities may lead to reduced ox-LDL generation.…”