加州大学Alan R. Saltiel团队宣布他们揭示了膳食胆固醇激活驱动LDLR周转的Ral依赖途径。这一研究成果于2026年6月24日发表在国际顶尖学术期刊《自然》上。
在这里，研究组确定了一个由Ral GTP酶调节的新途径，该途径将细胞外胆固醇信号与控制LDLR转换的细胞内运输机制联系起来。慢性膳食胆固醇通过增加RAS活性，将LDLR输送到溶酶体降解并抑制其再循环来激活Ral蛋白，而不依赖于转录调控或PCSK9。通过RalGAPB缺失或肝细胞中组成型活性Ral突变体的过表达，Ral的组成型激活可降低LDLR水平并损害胆固醇清除。
Ral参与内吞的RalBP1-REPS1复合体，促进LDLR内化和溶酶体路径，其中LDLR被溶酶体蛋白酶组织蛋白酶A （CTSA）降解。Ral激活引导CTSA走向溶酶体成熟，同时限制其分泌，进一步促进LDLR在溶酶体中的降解。这一途径的遗传变异与人类胆固醇的改变显著相关。药理抑制CTSA活性可增加肝脏LDLR功能并改善胆固醇清除，为高胆固醇血症和心血管疾病提供了一种潜在的新治疗策略。
研究人员表示，肝脏低密度脂蛋白受体（LDLR）的代谢是胆固醇稳态的关键决定因素。根据营养提示（包括高膳食胆固醇），协调LDLR运输和转换的分子开关仍未明确。
附：英文原文
Title: Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover
Author: Feng, Xue, Zhang, Shuo, Wang, Yuqi, Kurlagunda, Twisha, Sit, Allyssa, Jaishankar, Priyadarshini, Yang, Pusu, Sakane, Sadatsugu, Park, Se Yong, Wisessaowapak, Churaibhon, Nguyen, Kaylee, Yan, Jamie, Pothulu, Himani, Dinh, Catherine, Chu, Felicia, Ren, Yuyao, Zhang, Bichen, Secrest, Patrick, Han, Linmeng, Hung, Chao-Wei, Veeragandham, Preethi, Skorobogatko, Yuliya, Kisseleva, Tatiana, Gordts, Philip L.S.M., Renslo, Adam R., Zhao, Peng, Majithia, Amit R., Saltiel, Alan R.
Issue&Volume: 2026-06-24
Abstract: Metabolism of the hepatic low-density lipoprotein receptor (LDLR) is a key determinant of cholesterol homeostasis1,2. The molecular switches that coordinate LDLR trafficking and turnover in response to nutritional cues, including high dietary cholesterol, remain poorly defined3,4,5,6. Here we identify a new pathway regulated by Ral GTPases that links extracellular cholesterol signals to the intracellular trafficking machinery controlling LDLR turnover. Chronic dietary cholesterol activates the Ral proteins by increasing RAS activity, routing LDLR to lysosomes for degradation and inhibiting its recycling independently of transcriptional regulation or PCSK9. Constitutive activation of Ral via RalGAPB deletion or overexpression of constitutively active Ral mutants in hepatocytes reduces LDLR levels and impairs cholesterol clearance. Ral engages the endocytic RalBP1–REPS1 complex to promote LDLR internalization and lysosomal routing, where LDLR is degraded by the lysosomal protease cathepsin A (CTSA). Ral activation directs CTSA towards lysosomes for maturation while limiting its secretion, further promoting LDLR degradation in lysosomes. Genetic variants in this pathway significantly associate with altered cholesterol in humans. Pharmacological inhibition of CTSA activity increases hepatic LDLR function and improves cholesterol clearance, offering a potential new therapeutic strategy for hypercholesterolaemia and cardiovascular disease.
DOI: 10.1038/s41586-026-10697-z
Source: https://www.nature.com/articles/s41586-026-10697-z
期刊信息
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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