Lipids play an essential role in metabolism. For example, triglycerides (TG), consisting of glycerol triesters of FAs, such as palmitic and oleic acids, are responsible for 90% of dietary lipid and are the major form of metabolic energy storage in humans. Like glucose, TGs are metabolically oxidized to CO2 and H2O, but since the TG carbons have lower oxidation states than the carbons of glucose, the oxidative metabolism of fats produces over twice the energy of an equal weight of dry protein or carbohydrate.
While lipids can be endogenously synthesized from carbohydrates or amino acids, the majority of lipids in mammals are obtained from dietary absorption. The major dietary fat is TG, a water-insoluble ester derived from glycerol and three fatty acids. After TG emulsification by bile salts with subsequent hydrolysis by pancreatic lipase and colipase, the resulting fatty acids and monoglycerides are absorbed by the duodenum and re-emulsified by bile salts to form micelles. In the intestinal enterocytes, these micelles are absorbed and re-made into TG. The re-esterified TG, along with cholesterol and various lipoproteins, are then packaged into chylomicrons and excreted into the lymphatic system, where it can mix with the blood.
Lipoprotein lipase on endothelial cells delivers fatty acids to various cells, such as muscle cells and adipocytes, by hydrolyzing the triglyceride component of chylomicrons, resulting in cholesterol-enriched chylomicron remnants. Chylomicron remnants are subsequently cleared via endocytosis by hepatocytes. Non-esterified fatty acids, typically the result of lipolysis by adipose tissue in response to certain stimuli (i.e., catecholamines, glucagon), are also present in the bloodstream usually bound by serum albumin, which can also be taken up by the liver.
The main fates of fatty acids in the liver include: 1) esterification into TG as storage in the form of cytoplasmic lipid droplets, 2) release of apolipoprotein-associated triglycerides into the systemic circulation in the form of very low density lipoproteins (VLDL) to provide a constant supply of FA to peripheral tissues, and 3) fatty acid oxidation resulting in acetyl coA production. Fatty acid oxidation may occur in the mitochondria, peroxisomes, and the endoplasmic reticulum. While short- and medium-chain FAs pass the mitochondrial membrane without activation, long-chain FAs must be activated by carnitine palmitoyltransferase-1 (CPT1) in order to cross the mitochondrial membrane. Short-, medium-, and long-chain FAs are oxidized within the mitochondria via β-oxidation, while the more toxic very long-chain FAs are oxidized within peroxisomes. Acetyl-coA can be either completely degraded to CO2 in the tricarboxylic acid (TCA) cycle to provide NADH and FADH2 for ATP production in the electron transport chain (ETC), or condensed into ketone bodies, which are secreted by hepatocytes into the circulation and used as fuel for peripheral tissues (i.e., muscle, brain, and kidney). Depending on the energy state of the organism, the liver can modulate the rates of fatty acid uptake, esterification into TG, release of apolipoprotein-associated TG as VLDL, and fatty acid oxidation.