Early Pro-Inflammatory Remodeling of HDL Proteome in a Model of Diet-Induced Obesity: ²H₂O-Metabolic Labeling-Based...

Mice fed a high-fat diet for 12 weeks or longer develop hyperglycemia, insulin resistance, dyslipidemia, and fatty liver. Additionally, a high-fat diet induces inflammation that remodels and affects the anti-inflammatory and antiatherogenic property of the high-density lipoprotein (HDL). However, the precise time course of metabolic disease progression and HDL remodeling remains unclear. Short-term (four weeks) high-fat feeding (60% fat calories) was performed in wild-type male C57BL/6J mice to gain insights into the early metabolic disease processes in conjunction with a HDL proteome dynamics analysis using a heavy water metabolic labeling approach. The high-fat diet-fed mice developed hyperglycemia, impaired glucose tolerance, hypercholesterolemia without hypertriglyceridemia or hepatic steatosis. A plasma HDL proteome dynamics analysis revealed increased turnover rates (and reduced half-lives) of several acute-phase response proteins involved in innate immunity, including complement C3 (12.77 ± 0.81 vs. 9.98 ± 1.20 h, p < 0.005), complement factor B (12.71 ± 1.01 vs. 10.85 ± 1.04 h, p < 0.05), complement Factor H (19.60 ± 1.84 vs. 16.80 ± 1.58 h, p < 0.05), and complement factor I (25.25 ± 1.29 vs. 19.88 ± 1.50 h, p < 0.005). Our findings suggest that an early immune response-induced inflammatory remodeling of the plasma HDL proteome precedes the diet-induced steatosis and dyslipidemia.