Plasma lipidomic profiling in murine mutants of Hermansky-Pudlak syndrome reveals differential changes in pro- and anti-atherosclerotic lipids.

Atherosclerosis is characterized by the accumulation of lipid-rich plaques in the arterial wall. Its pathogenesis is very complicated and has not yet been fully elucidated. It is known that dyslipidemia is a major factor in atherosclerosis. Several different Hermansky-Pudlak syndrome (HPS) mutant mice have been shown either anti-atherosclerotic or atherogenic phenotypes, which may be mainly attributed to corresponding lipid perturbation. To explore the effects of different HPS proteins on lipid metabolism and plasma lipid composition, we analyzed the plasma lipid profiles of three HPS mutant mice, pa (Hps9^-/-), ru (Hps6^-/-), ep (Hps1^-/-), and wild-type (WT) mice. In pa and ru mice, some pro-atherosclerotic lipids, e.g. ceramide (Cer) and diacylglycerol (DAG), were down-regulated whereas triacylglycerol (TAG) containing docosahexaenoic acid (DHA) (22:6) fatty acyl was up-regulated when compared with WT mice. Several pro-atherosclerotic lipids including phosphatidic acid (PA), lysophosphatidylserine (LPS), sphingomyelin (SM), and cholesterol (Cho) were up-regulated in ep mice compared with WT mice. The lipid droplets in hepatocytes showed corresponding changes in these mutants. Our data suggest that the pa mutant resembles the ru mutant in its anti-atherosclerotic effects, but the ep mutant has an atherogenic effect. Our findings may provide clues to explain why different HPS mutant mice exhibit distinct anti-atherosclerotic or atherogenic effects after being exposed to high-cholesterol diets.

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