A novel truncated form of apolipoprotein A-I transported by dense LDL is increased in diabetic patients

Area of Science:

• Biochemistry
• Cardiovascular Science
• Metabolomics

Background:

• Diabetes Mellitus (DM) is associated with accelerated atherosclerosis and increased cardiovascular disease (CVD) burden.
• Key features of diabetes include altered lipid metabolism, lipoprotein structure, and high-density lipoprotein (HDL) dysfunction.

Purpose of the Study:

• To investigate biochemical modifications of Apolipoprotein A-I (ApoA-I), the primary HDL protein, in diabetic patients.
• To identify and characterize novel ApoA-I variants in serum from individuals with and without diabetes.

Main Methods:

• Proteomic technologies and mass spectrometry (MS) were employed to identify and characterize ApoA-I variants.
• In silico data mining and animal models were used to investigate potential enzymatic mechanisms of ApoA-I truncation.
• Lipoprotein analysis (VLDL, HDL, LDL subfractions) and functional assays (antioxidant activity, LDL oxidation) were performed.

Main Results:

• A novel truncated ApoA-I variant, ApoA-IΔ(1-38) (lacking amino acids 1-38), was identified in human serum.
• Diabetic patients showed a two-fold increase in serum ApoA-IΔ(1-38) compared to non-diabetic individuals.
• ApoA-IΔ(1-38) was found predominantly in LDL, particularly in dense LDL3 and LDL4 subfractions.
• Increased hepatic cathepsin D activity was identified as a potential protease responsible for ApoA-I truncation.
• Cathepsin D-mediated ApoA-I truncation resulted in increased LDL binding affinity and reduced antioxidant activity against LDL oxidation.

Conclusions:

• This study reveals a novel truncated ApoA-I form (ApoA-IΔ(1-38)) in human serum, increased in diabetic patients.
• ApoA-IΔ(1-38) is associated with LDL, particularly dense subfractions, in individuals with diabetes.
• Cathepsin D-mediated truncation of ApoA-I may contribute to increased LDL oxidation and heightened cardiovascular risk in diabetic patients.