HDL subclass proteomic analysis and functional implication of protein dynamic change during HDL maturation

Abstract

Recent clinical trials reported that increasing high-density lipoprotein-cholesterol (HDL-C) levels does not improve cardiovascular outcomes. We hypothesize that HDL proteome dynamics determine HDL cardioprotective functions. In this study, we characterized proteome profiles in HDL subclasses and established their functional connection. Mouse plasma was fractionized by fast protein liquid chromatography, examined for protein, cholesterial, phospholipid and trigliceride content. Small, medium and large (S/M/L)-HDL subclasseses were collected for proteomic analysis by mass spectrometry. Fifty-one HDL proteins (39 in S-HDL, 27 in M-HDL and 29 in L-HDL) were identified and grouped into 4 functional categories (lipid metabolism, immune response, coagulation, and others). Eleven HDL common proteins were identified in all HDL subclasses. Sixteen, 3 and 7 proteins were found only in S-HDL, M-HDL and L-HDL, respectively. We established HDL protein dynamic distribution in S/M/L-HDL and developed a model of protein composition change during HDL maturation. We found that cholesterol efflux and immune response are essential functions for all HDL particles, and amino acid metabolism is a special function of S-HDL, whereas anti-coagulation is special for M-HDL. Pon1 is recruited into M/L-HDL to provide its antioxidative function. ApoE is incorporated into L-HDL to optimize its cholesterial clearance function. Next, we acquired HDL proteome data from Pubmed and identified 12 replicated proteins in human and mouse HDL particle. Finally, we extracted 3 shared top moleccular pathways (LXR/RXR, FXR/RXR and acute phase response) for all HDL particles and 5 top disease/bio-functions differentially related to S/M/L-HDL subclasses, and presented one top net works for each HDL subclass. We conclude that beside their essencial functions of cholesterol efflux and immune response, HDL aquired antioxidative and cholesterol clearance functions by recruiting Pon1 and ApoE during HDL maturation.

Integrating Metabolomics, Genomics, and Disease Pathways in Age-Related Macular Degeneration

“…43 The different associations among lipoprotein subparticle sizes support the notion that the composition of lipoproteins may be important, and this can affect their functional role. 44 Further research into the composition of HDL and VLDL subparticles among different diseases is warranted to understand the meaning of these associations. 12 Decreased MUFA, SFA, and TotFA levels were identified in AMD patients compared with control participants in the current metabolomics study.…”

“…A potential interaction between HDL and the complement system was shown in proteomic studies that demonstrated that HDL lipoprotein particles contain various complement components. 44 Notably, large HDL subparticles were shown to contain complement factor H (CFH), whereas small HDL and medium HDL subparticles did not. Although Zhang et al 44 propose that the increased CFH concentration would provide large HDL subparticles with anti-inflammatory properties, our study suggested the opposite: increased large HDL levels were associated with increased systemic complement activity.…”

Paraoxonase 1 and atherosclerosis‐related diseases

“…The direct relationship between PON1 and oxidative stress is an indicator that PON1 plays a role in general antioxidative protection. In a study by Zhang and colleagues, HDL subclass proteomics confirmed that PON1 is situated within medium/large HDL particles where it is responsible for its antioxidative properties …”

“…In a study by Zhang and colleagues, HDL subclass proteomics confirmed that PON1 is situated within medium/large HDL particles where it is responsible for its antioxidative properties. 67 After our PON1/CVD-related work, we continued with studies focusing on acute ischemia and stroke. This is another complication within the vascular system with a defective atherosclerotic background.…”

Dissimilar Effects of Anagliptin and Sitagliptin on Lipoprotein Subclass in Standard or Strong Statin-Treated Patients with Type-2 Diabetes Mellitus: A Subanalysis of the REASON (Randomized Evaluation of Anagliptin versus Sitagliptin on Low-Density LipoproteiN Cholesterol in Diabetes) Trial

“…This effect coincided with changes in TG levels in VLDL subclasses, which was also observed with sitagliptin treatment. Although the atherogenicity of HDL subclasses are still a matter of controversy, the changes observed here in HDL subclasses may play a functional role [20].…”