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

Abstract

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.

Effects of ABCG1 knockout on proteomic composition of HDL in mice on a chow diet and a high‐fat diet

“…HDL modified by SAA was impaired in mediating cellular cholesterol efflux and inhibiting cellular inflammation [25]. In rodents, significantly increased SAA, murinoglobulin-1, and antitrypsin levels were detected in HDL during inflammation or metabolic disorders [26][27][28].…”

“…HDL modified by SAA was impaired in mediating cellular cholesterol efflux and inhibiting cellular inflammation [25]. In rodents, significantly increased SAA, murinoglobulin‐1, and antitrypsin levels were detected in HDL during inflammation or metabolic disorders [26–28]. Therefore, the enrichment of 7‐ketocholesterol in HDL, which is positively correlated with these inflammatory mediators, might indicate a proinflammatory state and atherogenic property of HDL.…”

Hypercaloric low-carbohydrate high-fat diet protects against the development of nonalcoholic fatty liver disease in obese mice in contrast to isocaloric Western diet

“…Interestingly, we found a significant increase of the HDL levels in the WD, compared with both SD and KD mice, while increased HDL levels are commonly associated with a reduction of the cardiovascular risks ( 33 ). The increased HDL cholesterol levels have been previously described in C57Bl/6 mice as well as human upon WD feeding ( 34 , 35 ). This phenomenon may be an adaptive response to the greater need to transport the high lipids content, suggesting that the association between HDL levels and metabolic risk is more complicated than originally proposed, and as such, increased HDL-C levels should be interpreted with care ( 34 ).…”

SARS‐CoV‐2 induced HDL dysfunction may affect the host's response to and recovery from COVID‐19

“…Reduced CEC of HDL in different inflammatory disorders might be due to reduced HDL paraoxonase-1 (PON-1) activity or increased content of associated serum amyloid A (SAA) in HDL. 26 Interestingly, HDL and RCT functions have many pleiotropic functions, including antioxidant, anti-inflammatory, antiapoptotic, anticytotoxic, and vasodilatory functions (Figure 4). 27 The anti-inflammatory effect of HDL is through receptors-dependent mechanisms.…”

“…Of note, small HDL particles promote CEC through the ABCA1 transporter, 25 suggesting that improving CEC reduces the risk of CVDs. Reduced CEC of HDL in different inflammatory disorders might be due to reduced HDL paraoxonase‐1 (PON‐1) activity or increased content of associated serum amyloid A (SAA) in HDL 26 . Interestingly, HDL and RCT functions have many pleiotropic functions, including antioxidant, anti‐inflammatory, antiapoptotic, anticytotoxic, and vasodilatory functions (Figure 4).…”