Intestinal Phospholipid Remodeling Is Required for Dietary-Lipid Uptake and Survival on a High-Fat Diet

Abstract

Summary Phospholipids are important determinants of membrane biophysical properties, but the impact of membrane acyl chain composition on dietary lipid absorption is unknown. Here we demonstrate that the LXR-responsive phospholipid-remodeling enzyme Lpcat3 modulates intestinal fatty acid and cholesterol absorption and is required for survival on a high-fat diet. Mice lacking Lpcat3 in the intestine thrive on carbohydrate-based chow, but lose body weight rapidly and become moribund on a triglyceride-rich diet. Lpcat3-dependent incorporation of polyunsaturated fatty acids into phospholipids is required for the efficient transport of dietary lipids into enterocytes. Furthermore, loss of Lpcat3 amplifies the production of gut hormones including GLP-1 and oleoylethanolamide in response to high-fat feeding, contributing to the paradoxical cessation of food intake in the setting of starvation. These results reveal that membrane phospholipid composition is a gating factor in passive lipid absorption, and implicate LXR-Lpcat3 signaling in a gut-brain feedback loop that couples absorption to food intake.

ER phospholipid composition modulates lipogenesis during feeding and in obesity

“…Together with prior work (19,31), these findings contribute to an emerging view of dynamic manipulation of membrane acyl chain composition as a regulatory strategy in the control of metabolic pathways.…”

Tg6F ameliorates the increase in oxidized phospholipids in the jejunum of mice fed unsaturated LysoPC or WD

“…9A); Tg6F only prevented some of the increase induced by WD. Thus, the effect of Tg6F is not comparable to removing Lpcat3 from the intestine, and we think that the deleterious effects seen with Lpcat3 knockout in the intestine (22,23) are not likely to be seen with Tg6F. Future research will be needed to sort out these issues.…”

“…10). Lpcat3 is important in remodeling the fatty acids in phospholipids, particularly in the small intestine (22,23). Thus, feeding LDLR-null mice either chow supplemented with 1 mg LysoPC 18:1 or feeding the mice WD raised the levels of LysoPC 18:1 in the tissue of the jejunum and the plasma to similar levels, but likely by quite different mechanisms.…”

“…Inasmuch as the absence of Lpcat3 in the intestine is deleterious because of the need to remodel saturated phospholipids to unsaturated phospholipids on a high-fat diet (22,23), one might ask whether the ability of Tg6F to reduce this remodeling process could also be deleterious. Tg6F did not eliminate the formation of LysoPC18:1 on WD in either the tissue of the jejunum (Fig.…”

Nuclear receptors and liver disease: Summary of the 2017 basic research symposium

“…Lpcat3 activity also contributes to the abundance of polyunsaturated PC species in obese (ob)/ob liver ER. In response to feeding, the abundance of ER polyunsaturated PC is increased in the absence of changes in Lpcat3 messenger RNA (mRNA) 12. The ER phospholipids, linoleoyl and arachidonoyl PCs, are stimulators of SREPB maturation, levels of which are regulated during feeding and in diet‐induced obesity.…”