Lipid Metabolism
The major sources of fatty acids in the liver include (1) de novo
lipogenesis, (2) lipoproteins taken up by the liver, (3) exogenous (plasma) free
fatty acids, and (4) the hydrolysis of cytoplasmic triglycerides.[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103]
[104]
[105]
With
its glycogen stores full, the liver will efficiently convert glucose to fatty acids
and triglycerides. Dietary fatty acids absorbed from the intestines reach the liver
by the lymph and blood, mostly in the form of chylomicrons. The nutritional and
hormonal status determines whether the liver oxidizes, stores, or releases free fatty
acids.[94]
[106]
[107]
The liver uses two major pathways for dispensation of fatty acids:
esterification and beta-oxidation. Esterification of fatty acids and glycerol produces
triglycerides (fat). The liver either stores this fat or incorporates it into lipoproteins—principally
very-low-density lipoproteins (VLDLs) for transport to other tissues. Free fatty
acids regulate VLDL production, whereas nutritional and hormonal signals regulate
VLDL secretion. Insulin and estrogens, for example, stimulate the hepatic secretion
of VLDLs.[94]
[108]
The beta-oxidation pathway in mitochondria sequentially degrades fatty acids to
acetyl coenzyme A (CoA). Glucagon markedly stimulates beta-oxidation, whereas insulin
inhibits it.
Acetyl-CoA is central to lipid metabolism; it plays key roles
in both synthetic (triglycerides, phospholipids, cholesterol, lipoproteins) and catabolic
(e.g., tricarboxylic acid cycle) pathways. Mitochondria oxidize acetyl groups to
adenosine triphosphate (ATP), carbon dioxide, and water. High rates of fatty acid
oxidation produce more acetyl-CoA than the tricarboxylic acid cycle can efficiently
metabolize.[13]
One result of this is ketogenesis—the
formation of ketone bodies; namely acetoacetate, beta-hydroxybutyrate, and acetone.
However, the catabolism of ketones requires ketoacyl-CoA transferase (also called
acetoacetate:succinyl-CoA transferase), an enzyme present in all tissues except liver.
[12]
Being unable to extract energy from ketones,
the liver releases the ketones into the bloodstream, providing an important energy
source for extrahepatic tissues during prolonged starvation. Starvation-induced
ketosis is self-limited because ketones promote the release of insulin from the pancreas.
Insulin inhibits lipolysis in adipose tissue[109]
and cuts off the hepatic supply of fatty acids for ketone synthesis.[91]
Without insulin, this feedback loop cannot work, and diabetic ketoacidosis occurs.
[13]
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