Dihydrosterculic acid induces hepatic PPARa target gene expression in mice

Authors: HALLS, LEAH - University Of Georgia; SON, YURA - University Of Georgia; LORENZ, W - University Of Georgia; Shockey, Jay; HEO, JUNWON - University Of Georgia; CALL, JARROD - University Of Georgia; PATON, CHAD - University Of Georgia

Submitted to: Journal of Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/14/2025
Publication Date: 8/22/2025
Citation: Halls, L.S., Son, Y., Lorenz, W.W., Shockey, J.M., Heo, J., Call, J.A., Paton, C.M. 2025. Dihydrosterculic acid induces hepatic PPARa target gene expression in mice. Journal of Physiology. https://doi.org/10.1113/JP287121.
DOI: https://doi.org/10.1113/JP287121

Interpretive Summary: High cholesterol poses a major health risk to millions of Americans and other people around the world. It contributes to many adverse health conditions, including heart disease and fatty liver disease. Previous studies have suggested that unique components of cottonseed oil, as a part of the diet for both humans and mouse subjects, reduces this risk. The types of metabolic changes caused by cottonseed oil consumption are not well known. In this study, we analyzed changes in lipids and gene expression in livers of mutant and normal mice, fed different diets with and without the unique components of cottonseed oil. Several categories of genes respond differently depending on the genetic status of the mouse and the type of plant oil included in the diet. These results provide valuable new information that will help to develop new treatments and cures for fatty liver disease in the future.

Technical Abstract: Cottonseed oil (CSO) is a seed oil with a unique lipid composition and the ability to reduce lipid levels in humans and mice. This study aimed to characterize the effects of dihydrosterculic acid (DHSA), a cyclopropyl fatty acid found in CSO, on lipid metabolism. First, male wild-type (WT) mice were placed on CSO- or isocaloric oil-enriched diets (lacking DHSA) for 6 weeks. Tissues were analyzed via RNA-sequencing which identified 45 differentially expressed genes within the CSO group, a majority of which are associated with lipid metabolic processes. These animals displayed decreased plasma triglyceride (p<0.05), with no difference in hepatic triglyceride or non-esterified fatty acids (NEFA) compared to chow despite being a moderate fat diet. Confirmational tissue analysis showed an increase in hepatic PPARa and target gene expression in the CSO group compared to control diet groups, suggesting that DHSA’s effects may be mediated through PPARa to increase its transcriptional activity and fatty acid oxidation (FAO). In vitro, PPARa-dependent CPT1A gene expression increased following treatment with DHSA, while SCD1 expression was reduced, suggesting CSO works by inhibiting lipogenesis and increasing FAO via PPARa. To test this hypothesis, female PPARa knockout (KO) mice were fed a CSO-enriched diet and compared to either chow or a lipid matched control diet. In the absence of PPARa, the lipid lowering effect of the CSO diet was ablated, as evidenced by increased hepatic TG and NEFA. In total, these data suggest that CSO functions through linoleic acid/DHSA-dependent activation of FAO pathways which require the transcription factor PPARa.