Summary
A bioRxiv preprint reports that rare and common STARD9 variants are associated with different lipid disorders and opposite changes in lysosome positioning. The authors connect those differences to cholesterol handling in cells and, in knockout mice, to intestinal cholesterol absorption.
A bioRxiv preprint posted September 26, 2026 reports that rare and common variants in STARD9 are associated with different lipid disorders and opposite changes in lysosome positioning. The authors connect those differences to how cells handle cholesterol, and report increased intestinal cholesterol absorption in Stard9-knockout mice.
The genetic findings link rare STARD9 variants with autosomal dominant hypercholesterolemia and premature coronary disease. Common variants are associated with lower HDL cholesterol and higher triglycerides. The authors propose that STARD9, a lysosomal cholesterol-sensing kinesin, helps coordinate cholesterol traffic by controlling where lysosomes sit inside cells.
How lysosome position could change cholesterol handling
Lysosomes break down and recycle cellular material. Cholesterol stored in them can also affect how much is available to other parts of the cell, including the endoplasmic reticulum (ER), a membrane network involved in sensing and regulating cholesterol. The authors report that both variant patterns converge on cholesterol sequestration in lysosomes and reduced cholesterol availability in the ER, alongside activation of mTORC1 and SREBP2, impaired autophagy and NF-κB-related inflammation.
The reported lysosome movements differ. Rare variants disperse lysosomes toward the cell’s periphery, while the common-variant pattern keeps them closer to the nucleus. The authors associate the rare-variant pattern with LDL-receptor degradation and cholesterol efflux involving CASM and TFEB, which they say preserves HDL. By contrast, perinuclear retention is linked to reduced TFEB-dependent lipid-handling activity, higher triglycerides and lower HDL.
Findings in mice and possible relevance
In Stard9-knockout mice, the authors report that cholesterol sequestration in intestinal enterocytes—cells lining the gut—leads to SREBP2-dependent increases in NPC1L1, a protein involved in intestinal cholesterol uptake. NPC1L1 also moves toward the cells’ apical surface, and the authors report increased absorption of cholesterol from the intestine.
The findings point to lysosomal cholesterol traffic as a possible research target in cardiovascular disease, including risk that persists despite lipid-lowering therapy. The evidence described is genetic and mechanistic, with an intestinal result in knockout mice; it is not a test of a treatment in people. The work is a preprint, and its abstract does not provide cohort or sample counts.