Myeloid-specific loss of Pck1 does not alter aortic root atherosclerosis in mice, preprint reports

A preprint deposited on bioRxiv from Cold Spring Harbor Laboratory investigates the contribution of phosphoenolpyruvate carboxykinase 1 (Pck1) to atherosclerosis susceptibility within the Ath28.1 quantitative trait locus (QTL) on mouse chromosome 2. The Ath28.1 subregion, identified through congenic strain fine mapping of a cross between atherosclerosis-resistant AKR Apoe−/− mice and atherosclerosis-sensitive DBA/2 Apoe−/− mice, spans approximately 217 kilobases and encodes only three protein-coding genes: Zbp1, Pck1, and Pmepa1.

To test whether myeloid-cell expression of Pck1 — an enzyme central to gluconeogenesis and a known regulator of macrophage metabolic state — contributes to plaque formation, the authors generated mice with a macrophage-specific Pck1 deletion on an Apoe−/− background and assessed aortic root lesion area. The preprint reports no significant difference in atherosclerotic burden between conditional knockout and control animals.

The negative result narrows the candidate field within Ath28.1 and shifts attention towards Zbp1 and Pmepa1 as the more likely effectors of the QTL's atherosclerosis-modifying activity. The work illustrates the iterative process of positional cloning and functional validation in complex-trait genetics in mouse models.

This is a preprint and has not yet undergone peer review. Results should be interpreted with appropriate caution pending independent review.