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Molecular processes that handle — and mishandle — dietary lipids
Kevin Jon Williams
Kevin Jon Williams
Published October 1, 2008
Citation Information: J Clin Invest. 2008;118(10):3247-3259. https://doi.org/10.1172/JCI35206.
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Science in Medicine

Molecular processes that handle — and mishandle — dietary lipids

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Abstract

Overconsumption of lipid-rich diets, in conjunction with physical inactivity, disables and kills staggering numbers of people worldwide. Recent advances in our molecular understanding of cholesterol and triglyceride transport from the small intestine to the rest of the body provide a detailed picture of the fed/fasted and active/sedentary states. Key surprises include the unexpected nature of many pivotal molecular mediators, as well as their dysregulation — but possible reversibility — in obesity, diabetes, inactivity, and related conditions. These mechanistic insights provide new opportunities to correct dyslipoproteinemia, accelerated atherosclerosis, insulin resistance, and other deadly sequelae of overnutrition and underexertion.

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Kevin Jon Williams

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Figure 1

Overview of lipid transport from gut lumen to periphery to liver.

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Overview of lipid transport from gut lumen to periphery to liver.
Deterg...
Detergents in hepatic bile, chiefly phospholipids (PL) and bile acids, emulsify lipids from food to form microscopic micelles within the gut lumen. Hepatic bile also contributes significant amounts of UC to these micelles. The pancreas secretes lipases that digest dietary lipids into chemical forms that can be absorbed by the gut epithelium, e.g., NEFAs, monoacylglycerides, and UC. Absorption of fatty acids and monoacylglycerides approaches 100% efficiency and occurs via passive diffusion and carrier-mediated processes (64). Cholesterol absorption averages about 50% efficiency with considerable interindividual variation. Enterocytes reesterify these lipids intracellularly and then package them into large particles, CMs, that are rich in triglycerides (TG) but also contain substantial amounts of UC and cholesteryl esters. These particles are secreted into thoracic lymph, which drains directly into the systemic bloodstream, bypassing the liver. The mixed lipid composition of CMs leads to a 2-step clearance process. First, when these particles reach the capillary beds of peripheral tissues, a key metabolic branch point occurs between energy storage in adipose tissue (blue arrows) and lipid combustion in striated muscle (green arrows). In a regulated fashion, CMs dock on the microvascular endothelium of these tissues, where LpL hydrolyzes CM triglycerides into NEFAs to deliver lipid calories for local use. In the second step of clearance, residual triglyceride-depleted, cholesteryl ester–rich particles, now called CM remnant lipoproteins, are released back into plasma. Under normal circumstances, the liver rapidly and safely removes them from the circulation (red arrows).
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