Elevated triglycerides predict insulin resistance and vascular disease in obesity, but how the inert triglyceride molecule is related to development of metabolic disease is unknown. To pursue novel potential mediators of triglyceride-associated metabolic disease, we used a forward genetics approach involving inbred mice and translated our findings to human subjects.
Hemopexin (HPX) was identified as a differentially expressed gene within a quantitative trait locus associated with serum triglycerides in an F16 advanced intercross between the LG/J and SM/J strains of mice. Hpx expression was evaluated in both the reproductive fat pads and livers of mice representing three strains, LG/J (n=25), SM/J (n=27) and C57Bl/6J (n=19), on high- and low-fat diets. The effect of altered Hpx expression on adipogenesis was studied in 3T3-L1 cells. Circulating HPX protein along with HPX expression were characterized in subcutaneous white adipose tissue samples obtained from a cohort of metabolically abnormal (n=18) and of metabolically normal (n=24) obese human subjects. We further examined the relationship between HPX and triglycerides in human atherosclerotic plaques (n=18).
HPX expression in mouse adipose tissue, but not in liver, was regulated by dietary fat regardless of genetic background. HPX increased in concert with adipogenesis in 3T3-L1 cells, and disruption of its expression impaired adipocyte differentiation. RNAseq data from the adipose tissue of obese humans showed differential expression of HPX based on metabolic disease status (P<0.05), and circulating HPX levels were correlated with serum triglycerides in these subjects (r=0.33; P=0.03). HPX was also found in an unbiased proteomic screen of human atherosclerotic plaques and shown to display differential abundance based on the extent of disease and triglyceride content (P<0.05).
Our findings suggest that HPX is associated with triglycerides and provide a framework for understanding mechanisms underlying lipid metabolism and metabolic disease.
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We thank Dr Irfan Lodhi for sharing his 3T3-L1 differentiation protocol and Dr Larry Spears for his assistance in trouble shooting the western blotting experiments. This work was supported by NIH-NIDDK K01 DK95003 and P30 DK56341 to HAL and in part by the EA annual grant contest (2012) co-sponsored by Illumina and Golden Helix to L-LG, SK and HAL. The content of this paper is solely the responsibility of the authors.
HAL designed the study, conducted experiments, analyzed data, wrote the manuscript and secured funding and collaborations. MZ performed the carotid endarterectomy operations, prepared the carotid artery plaque homogenates, conducted the pilot proteomics scan and assisted with manuscript preparation. JPW conducted experiments and assisted with manuscript preparation. EF collected and prepared MNO/MAO subject data. L-LG prepared the MNO/MAO RNA samples. SK provided MNO/MAO subject data and samples and assisted with manuscript preparation. CFS assisted in study design, contributed reagents, provided laboratory space and equipment for experiments and assisted in manuscript preparation.
About this article
Supplementary Information accompanies this paper on International Journal of Obesity website (http://www.nature.com/ijo)