Triglyceride Metabolism in the Liver

Abstract

Triglyceride molecules represent the major form of storage and transport of fatty acids within cells and in the plasma. The liver is the central organ for fatty acid metabolism. Fatty acids accrue in liver by hepatocellular uptake from the plasma and by de novo biosynthesis. Fatty acids are eliminated by oxidation within the cell or by secretion into the plasma within triglyceride-rich very low-density lipoproteins. Notwithstanding high fluxes through these pathways, under normal circumstances the liver stores only small amounts of fatty acids as triglycerides. In the setting of overnutrition and obesity, hepatic fatty acid metabolism is altered, commonly leading to the accumulation of triglycerides within hepatocytes, and to a clinical condition known as nonalcoholic fatty liver disease (NAFLD). In this review, we describe the current understanding of fatty acid and triglyceride metabolism in the liver and its regulation in health and disease, identifying potential directions for future research. Advances in understanding the molecular mechanisms underlying the hepatic fat accumulation are critical to the development of targeted therapies for NAFLD. © 2018 American Physiological Society. Compr Physiol 8:1-22, 2018.

Thioesterase Superfamily Member 2 Promotes Hepatic VLDL Secretion by Channeling Fatty Acids Into Triglyceride Biosynthesis

“…To ascertain the mechanisms underlying the reduction in VLDL secretion, we investigated the regulation of genes involved in VLDL biogenesis . The mRNA levels of ApoB , microsomal TG transfer protein ( Mtp ), Sec24c , and Sec24d were decreased in the livers from L‐Them2 ‐/‐ mice by 14%‐24%, whereas the mRNA levels of Cidea and Sar1b were increased by 678% and 28%, respectively (Fig.…”

“…In support of a role of hepatic Them2 in the hydrolysis of fatty acyl‐CoAs in vivo , chow‐fed L‐Them2 ‐/‐ mice exhibited increases in the hepatic concentrations of long‐chain acyl‐CoA species, along with decreased intracellular free FA concentrations. The blunting of this effect in high fat–fed animals most likely reflects the contributions from other sources, such as increased hepatic uptake of adipose tissue–derived free FA from plasma in the context of diet‐induced insulin resistance, and the down‐regulation of other Acot isoforms in the livers of high fat–fed L‐Them2 ‐/‐ mice, which presumably reflects an adaptive response that prevented the accumulation of more toxic‐free FA molecules in the liver.…”

“…Alterations in hepatic fatty acid (FA) metabolism contribute to the development of metabolic disorders, including nonalcoholic fatty liver disease (NAFLD), type 2 diabetes, and atherosclerotic cardiovascular disease. Long‐chain FAs accrue in the liver by uptake from the plasma, de novo synthesis, or the turnover of complex lipids . Within the hepatocyte, free FA molecules experience one of several metabolic fates, including complex lipid biosynthesis and oxidation, but also may regulate intracellular processes, such as protein localization, intracellular signaling, and transcription factor activation .…”

Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease

“…Increased acetate in the liver can cause triglyceride accumulation because acetate is an important substrate for fatty acid synthesis 98. Increased levels of propionate promote gluconeogenesis in the liver, since propionate is a precursor for gluconeogenesis 97 99.…”

“…Endogenous ethanol inhibits the tricarboxylic acid cycle, thus increases levels of acetate, thereby promoting triglyceride accumulation in hepatocytes 98. Ethanol can also increase the activity of CYP2E1116 to catalyse ethanol oxidation and produce free radicals that might promote liver inflammation 117.…”