Disruption of cholesterol homeostasis by plant sterols
Chendong Yang, … , Jonathan C. Cohen, Helen H. Hobbs
Chendong Yang, … , Jonathan C. Cohen, Helen H. Hobbs
Published September 15, 2004
Citation Information: J Clin Invest. 2004;114(6):813-822. https://doi.org/10.1172/JCI22186.
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Article Metabolism

Disruption of cholesterol homeostasis by plant sterols

Abstract

The ABC transporters ABCG5 and ABCG8 limit absorption and promote excretion of dietary plant sterols. It is not known why plant sterols are so assiduously excluded from the body. Here we show that accumulation of plant sterols in mice lacking ABCG5 and ABCG8 (G5G8–/– mice) profoundly perturbs cholesterol homeostasis in the adrenal gland. The adrenal glands of the G5G8–/– mice were grossly abnormal in appearance (brown, not white) due to a 91% reduction in cholesterol content. Despite the very low cholesterol levels, there was no compensatory increase in cholesterol synthesis or in lipoprotein receptor expression. Moreover, levels of ABCA1, which mediates sterol efflux, were increased 10-fold in the G5G8–/– adrenals. Adrenal cholesterol levels returned to near-normal levels in mice treated with ezetimibe, which blocks phytosterol absorption. To determine which plant sterol(s) caused the metabolic changes, we examined the effects of individual plant sterols on cholesterol metabolism in cultured adrenal cells. Addition of stigmasterol, but not sitosterol, inhibited SREBP-2 processing and reduced cholesterol synthesis. Stigmasterol also activated the liver X receptor in a cell-based reporter assay. These data indicate that selected dietary plant sterols disrupt cholesterol homeostasis by affecting two critical regulatory pathways of lipid metabolism.

Authors

Chendong Yang, Liqing Yu, Weiping Li, Fang Xu, Jonathan C. Cohen, Helen H. Hobbs

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Figure 1

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Comparison of the adrenal glands from female G5G8–/– mice with those fro...
Comparison of the adrenal glands from female G5G8–/– mice with those from female wild-type mice. (A) Adrenal glands from 6-month-old female wild-type and G5G8–/– mice. (B) Sections from the adrenal cortex of a female wild-type mouse and a female G5G8–/– mouse after staining with Oil-Red O (×20 magnification). (C) Electron micrographs of the adrenal zona fasciculata of wild-type and G5G8–/– mice. Adrenal glands were removed from 6-month-old female wild-type and G5G8–/– mice, and electron microscopic sections were prepared and examined as described in Methods. Electron micrographs were taken at a magnification of ×2,500. Scale bars: 1 μm.