Glycation Reduces the Stability of ApoAI and Increases HDL Dysfunction in Diet-Controlled Type 2 Diabetes.
Adult; Aged; Animal Studies; Animals; Apolipoprotein A-I/blood/*metabolism; Apolipoproteins – Blood; Apolipoproteins – Metabolism; Biochemical Phenomena; Case Control Studies; Case-Control Studies; Cells; Comparative Studies; Cultured; Diabetes Mellitus; Diet; Dyslipidemias/complications/diet therapy/*metabolism; Evaluation Research; Female; Funding Source; Glycosylation; HDL – Metabolism; HDL/*metabolism; Human; Humans; Hyperglycemia – Complications; Hyperglycemia – Diet Therapy; Hyperglycemia – Metabolism; Hyperglycemia/complications/diet therapy/*metabolism; Hyperlipidemia – Complications; Hyperlipidemia – Diet Therapy; Hyperlipidemia – Metabolism; Lipoproteins; Male; Mice; Middle Age; Middle Aged; Multicenter Studies; Protein Stability; Type 2 – Complications; Type 2 – Diet Therapy; Type 2 – Metabolism; Type 2/complications/*diet therapy/metabolism; Validation Studies
Context: Hyperglycemia plays a key role in the pathogenesis of cardiovascular complications of diabetes. Type 2 diabetes mellitus (T2DM) is associated with high-density lipoprotein (HDL) dysfunction and increased degradation of apolipoprotein I (ApoAI). The mechanism(s) of these changes is largely unknown. Objective: To study the role of hyperglycemia-induced glycation on ApoAI kinetics and stability in patients with diet-controlled T2DM. Design: 2H2O-metabolic labeling approach was used to study ApoAI turnover in patients with diet-controlled T2DM [n = 9 (5 F); 59.3 +/- 8.5 years] and matched healthy controls [n = 8 (4 F); 50.7 +/- 11.6 years]. The effect of Amadori glycation on in vivo ApoAI stability and the antioxidant and cholesterol efflux properties of HDL were assessed using a proteomics approach and in vitro assays. Results: Patients with T2DM had increased turnover of ApoAI and impaired cholesterol efflux and antioxidant properties of HDL. Glycated hemoglobin was negatively correlated with the half-life of ApoAI and cholesterol efflux function of HDL. Proteomics analysis identified several nonenzymatic early (Amadori) glycations of ApoAI at lysine sites. The kinetics analysis of glycated and native ApoAI peptides in patients with T2DM revealed that glycation resulted in a threefold shorter ApoAI half-life. Conclusions: The 2H2O method allowed the detection of early in vivo impairments in HDL metabolism and function that were related to hyperglycemia-induced glycation of ApoAI in T2DM.
Kashyap Sangeeta R; Osme Abdullah; Ilchenko Serguei; Golizeh Makan; Lee Kwangwon; Wang Shuhui; Bena James; Previs Stephen F; Smith Jonathan D; Kasumov Takhar
The Journal of clinical endocrinology and metabolism
2018
2018-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1210/jc.2017-01551" target="_blank" rel="noreferrer noopener">10.1210/jc.2017-01551</a>
HDL Flux is Higher in Patients with Nonalcoholic Fatty Liver Disease
haevy water; HDL; NAFLD; NASH; proteomics
October 2019 Update
Altered lipid metabolism and inflammation are involved in the pathogenesis of both non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). Even though high-density lipoprotein (HDL), a CVD protective marker, is decreased, whether HDL metabolism and function are perturbed in NAFLD are currently unknown. We examined the effect of NAFLD and disease severity on HDL metabolism and function in patients with biopsy-proven simple steatosis (SS), nonalcoholic steatohepatitis (NASH), and healthy controls. HDL turnover and HDL proteins dynamics in SS (n=7), NASH patients (n=8), and healthy controls (n=9) were studied in vivo. HDL maturation and remodeling, anti-oxidant, cholesterol efflux properties, and activities of lecithin cholesterol ester acyl transferase (LCAT) and cholesterol ester transfer protein (CETP) were quantified using in vitro assays. All NAFLD patients had increased turnover of both HDL cholesterol (HDLc, 0.16±0.09 vs. 0.34±0.18 day-1, P<0.05) and ApoAI (0.26±0.04 vs. 0.34±0.06 day-1, P<0.005) compared to healthy controls. The fractional catabolic rates (FCR) of other HDL proteins, including ApoAII (and ApoAIV were higher (P<0.05) in NAFLD patients who also had higher CETP activity, ApoAI/HDLc ratio (P<0.05). NAFLD-induced alterations were associated with lower antioxidant (114.2±46.6 vs 220.5±48.2 nml/ml●min) but higher total efflux properties of HDL (23.4±1.3 vs. 25.5±2.3 %) (both P<0.05) which was more pronounced in individuals with NASH. However, no differences were observed in either HDL turnover, antioxidant and cholesterol efflux functions of HDL or HDL proteins' turnover between SS and NASH subjects. Thus, HDL metabolism and function are altered in NAFLD without any significant differences between SS and NASH.
McCullough Arthur; Previs Stephen F; Dasarathy Jaividhya; Lee Kwangwon; Osme Abdullah; Kim Chunki; Ilchenko Serguei; Lorkowski Shuhui W; Smith Jonathan D; Dasarathy Srinivasan; Kasumov Takhar
American Journal of Physiology. Endocrinology and Metabolism
2019
2019-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpendo.00193.2019" target="_blank" rel="noreferrer noopener">10.1152/ajpendo.00193.2019</a>