Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44160, USA.
FASEB J. 2010 Jun;24(6):1656-66. doi: 10.1096/fj.09-150995. Epub 2010 Jan 8.
The uptake of dietary lipids from the small intestine is a complex process that depends on the activities of specific membrane receptors with yet unknown regulatory mechanisms. Using both mouse models and human cell lines, we show here that intestinal lipid absorption by the scavenger receptor class B type 1 (SR-BI) is subject to control by retinoid signaling. Retinoic acid via retinoic acid receptors induced expression of the intestinal transcription factor ISX. ISX then repressed the expression of SR-B1 and the carotenoid-15,15'-oxygenase Bcmo1. BCMO1 acts downstream of SR-BI and converts absorbed beta,beta-carotene to the retinoic acid precursor, retinaldehyde. Using BCMO1-knockout mice, we demonstrated increased intestinal SR-BI expression and systemic beta,beta-carotene accumulation. SR-BI-dependent accumulation of beta,beta-carotene was prevented by dietary retinoids that induced ISX expression. Thus, our study revealed a diet-responsive regulatory network that controls beta,beta-carotene absorption and vitamin A production by negative feedback regulation. The role of SR-BI in the intestinal absorption of other dietary lipids, including cholesterol, fatty acids, and tocopherols, implicates retinoid signaling in the regulation of lipid absorption more generally and has clinical implications for diseases associated with dyslipidemia.
肠道对膳食脂质的摄取是一个复杂的过程，依赖于具有未知调节机制的特定膜受体的活性。在这里，我们使用小鼠模型和人细胞系表明，肠道脂质吸收通过清道夫受体 B 类 I 型（SR-BI）受到视黄酸信号的控制。视黄酸通过视黄酸受体诱导肠转录因子 ISX 的表达。ISX 然后抑制 SR-B1 和类胡萝卜素 15、15'-加氧酶 Bcmo1 的表达。BCMO1 作用于 SR-BI 的下游，将吸收的β，β-胡萝卜素转化为视黄酸前体，视黄醛。使用 BCMO1 敲除小鼠，我们证明了肠道 SR-BI 表达增加和全身β，β-胡萝卜素积累。膳食视黄醇通过诱导 ISX 表达来预防 SR-BI 依赖性的β，β-胡萝卜素积累。因此，我们的研究揭示了一个饮食反应性调节网络，通过负反馈调节控制β，β-胡萝卜素的吸收和维生素 A 的产生。SR-BI 在其他膳食脂质，包括胆固醇、脂肪酸和生育酚的肠道吸收中的作用表明视黄酸信号在脂质吸收的更普遍调节中起作用，并对与血脂异常相关的疾病具有临床意义。
