High-cholesterol diets trigger liver receptor loss, study finds

A new Nature paper found that chronic dietary cholesterol activates a Ral-dependent pathway that pushes LDL receptors in liver cells into lysosomal destruction instead of recycling. That matters because LDLR is one of the body’s main tools for clearing LDL cholesterol from the blood, and losing those receptors can leave harmful cholesterol circulating longer. The work also showed that the effect operated independently of transcriptional regulation and PCSK9, two of the best-known LDL receptor control routes.

In experiments using mice and human cells, researchers including Xue Feng, Shuo Zhang, Alan R. Tall, Matthew Blumenthal and Olivia Walther found that chronic dietary cholesterol increased RAS activity and switched on Ral proteins. Ral then engaged the endocytic RalBP1-REPS1 complex, drove LDLR internalization and sent the receptor to lysosomes, where cathepsin A, or CTSA, degraded it. The pathway also directed CTSA toward lysosomes for maturation while limiting its secretion, sharpening the effect on LDLR turnover.

The finding was not just a laboratory observation. Constitutive activation of Ral, through RalGAPB deletion or engineered active Ral mutants in hepatocytes, lowered LDLR levels and impaired cholesterol clearance. Genetic variants in the same pathway were significantly associated with altered cholesterol in humans, giving the mechanism a human-genetics signal as well as support from cell and animal work.

The result lands in a field that still carries enormous public-health and financial weight. The World Health Organization says cardiovascular diseases were the leading cause of death globally, with an estimated 19.8 million deaths in 2022. In the United States, the American College of Cardiology, the American Heart Association and nine other medical associations issued updated dyslipidemia guidance on March 13, 2026, while the AHA’s 2026 statistics update estimated that 63.1 million U.S. adults, or 25.5%, had LDL cholesterol of 130 mg/dL or higher based on 2017 to 2020 data. The Centers for Disease Control and Prevention says about 47 million U.S. adults who could benefit from cholesterol medicine are taking it.

Because statins and PCSK9 inhibitors work by preserving or increasing LDL receptors, the newly identified Ral pathway points to a different therapeutic lever. The University of California San Diego School of Medicine summary said the study used mice and human cells and identified a drug candidate already proven safe in humans, raising the possibility of repurposing a known compound. Taken together, the findings suggest that prolonged high dietary cholesterol may not only overload the liver’s cleanup system but may also push it toward destroying the receptors that keep LDL out of circulation.