Dataset Information

Diabetes Impairs Cellular Cholesterol Efflux From ABCA1 to Small HDL Particles.

ABSTRACT:

Rationale

HDL (high-density lipoprotein) may be cardioprotective because it accepts cholesterol from macrophages via the cholesterol transport proteins ABCA1 (ATP-binding cassette transporter A1) and ABCG1 (ATP-binding cassette transporter G1). The ABCA1-specific cellular cholesterol efflux capacity (ABCA1 CEC) of HDL strongly and negatively associates with cardiovascular disease risk, but how diabetes mellitus impacts that step is unclear.

Objective

To test the hypothesis that HDL's cholesterol efflux capacity is impaired in subjects with type 2 diabetes mellitus.

Methods and results

We performed a case-control study with 19 subjects with type 2 diabetes mellitus and 20 control subjects. Three sizes of HDL particles, small HDL, medium HDL, and large HDL, were isolated by high-resolution size exclusion chromatography from study subjects. Then we assessed the ABCA1 CEC of equimolar concentrations of particles. Small HDL accounted for almost all of ABCA1 CEC activity of HDL. ABCA1 CEC-but not ABCG1 CEC-of small HDL was lower in the subjects with type 2 diabetes mellitus than the control subjects. Isotope dilution tandem mass spectrometry demonstrated that the concentration of SERPINA1 (serpin family A member 1) in small HDL was also lower in subjects with diabetes mellitus. Enriching small HDL with SERPINA1 enhanced ABCA1 CEC. Structural analysis of SERPINA1 identified 3 amphipathic α-helices clustered in the N-terminal domain of the protein; biochemical analyses demonstrated that SERPINA1 binds phospholipid vesicles.

Conclusions

The ABCA1 CEC of small HDL is selectively impaired in type 2 diabetes mellitus, likely because of lower levels of SERPINA1. SERPINA1 contains a cluster of amphipathic α-helices that enable apolipoproteins to bind phospholipid and promote ABCA1 activity. Thus, impaired ABCA1 activity of small HDL particles deficient in SERPINA1 could increase cardiovascular disease risk in subjects with diabetes mellitus.

SUBMITTER: He Y

PROVIDER: S-EPMC7554159 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Objective: It has been reported that atrial natriuretic peptide (ANP) regulates lipid metabolism by stimulating adipocyte browning, lipolysis, and lipid oxidation, and by impacting the secretion of adipokines. In our previous study, we found that the plasma ANP concentration of hypertensive disorders of pregnancy (HDP) was significantly increased in comparison to that of normotensive pregnancy patients. Thus, this study's objective was to investigate the lipid profile in patients with HDP and determine the effects of ANP on the cholesterol efflux in THP-1 macrophages. Methods: A total of 265 HDP patients and 178 normotensive women as the control group were recruited. Clinical demographic characteristics and laboratory profile data were collected. Plasma total triglycerides (TGs), total cholesterol (TC), low-density cholesterol (LDL-C), and high-density cholesterol (HDL-C) were compared between the two groups. THP-1 monocytes were incubated with different concentrations of ANP. ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) mRNA and protein were evaluated. ABCA1- and ABCG1-mediated cholesterol efflux to apolipoprotein A-Ⅰ (apoA-Ⅰ) and HDL, respectively, were measured by green fluorescent labeled NBD cholesterol. Natriuretic peptide receptor A (NPR-A) siRNA and specific agonists of the peroxisome proliferator-activated receptor-γ (PPAR-γ) and liver X receptor α (LXRα) were studied to investigate the mechanism involved. Results: Plasma TG, TC, LDL-C, and LDL-C/HDL-C were significantly increased, and HDL-C was significantly decreased in the HDP group in comparison to the control (all p < 0.001). ANP inhibited the expression of ABCA1 and ABCG1 at both the mRNA and protein levels in a dose-dependent manner. The functions of ABCA1- and ABCG1-mediated cholesterol efflux to apoA-I and HDL were significantly decreased. NPR-A siRNA further confirmed that ANP binding to its receptor inhibited ABCA1/G1 expression through the PPAR-γ/LXRα pathway. Conclusions: ABCA1/G1 was inhibited by the stimulation of ANP when combined with NPR-A through the PPAR-γ/LXRα pathway in THP-1 macrophages. The ABCA1/G1-mediated cholesterol efflux was also impaired by the stimulation of ANP. This may provide a new explanation for the decreased level of HDL-C in HDP patients.