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.
Highlights
It is common for diet-induced metabolic disturbances to manifest as a spectrum of conditions including adiposity, hyperinsulinemia, hyperglycemia, hepatic steatosis, and dyslipidemia [1]
This model of high-fat diet (HFD)-induced obesity in mice is marked by hyperinsulinemia, hyperglycemia, non-alcoholic fatty liver disease (NAFLD), and a dysregulated lipoprotein profile—high low-density lipoprotein (LDL)-cholesterol, decreased high-density lipoprotein (HDL)-cholesterol (HDL-C), and hypertriglyceridemia
We focused on HDL-associated proteins as they are sensitive to diet-induced inflammation and are involved in reverse cholesterol transport, anti-inflammatory, antioxidant, and antithrombotic functions of HDL that protect against atherosclerosis [20]
Summary
It is common for diet-induced metabolic disturbances to manifest as a spectrum of conditions including adiposity, hyperinsulinemia, hyperglycemia, hepatic steatosis, and dyslipidemia [1]. The chronic nature of these conditions and the fact that they often go undetected for several years has emphasized the need for the early indicators of metabolic disturbances [3,4] The convergence of these multiple diet-induced metabolic disturbances is a significant clinical challenge. The pathophysiological changes produced due to caloric overload associated with high-fat intake mimics the clinical metabolic disease with high fidelity This model of HFD-induced obesity in mice is marked by hyperinsulinemia, hyperglycemia, non-alcoholic fatty liver disease (NAFLD), and a dysregulated lipoprotein profile—high low-density lipoprotein (LDL)-cholesterol, decreased high-density lipoprotein (HDL)-cholesterol (HDL-C), and hypertriglyceridemia. We focused on HDL-associated proteins as they are sensitive to diet-induced inflammation and are involved in reverse cholesterol transport, anti-inflammatory, antioxidant, and antithrombotic functions of HDL that protect against atherosclerosis [20]
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