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HDL adverse remodelling and dysfunction is a temporal feature that can be reversed


 
 
 Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministerio de Ciencia e Innovación (MCIN)/AEI/10.13039/501100011033 and Fondo Europeo de Desarrollo Regional (FFEDER)
 
 
 
 High-density lipoprotein (HDL) particles have been shown to undergo adverse remodelling and loss of function in the presence of comorbidities. It has been demonstrated that high low-density lipoprotein cholesterol (LDL-C) plasma levels induce compositional changes in HDL particles that render them dysfunctional. It is unknown, however, whether this HDL adverse remodelling is reversible.
 
 
 
 In this preclinical animal study we have investigated whether dyslipidaemia-induced HDL particle remodelling and dysfunction is a permanent adverse change or a temporal trait which can be regulated by dietary intervention.
 
 
 
 After 10 days of high-fat diet (HFD) and reaching LDL-C levels of 392.8±94.9 mg/dL, the HDL particles of 15 pigs were characterized. Thereafter, pigs were randomly distributed into two arms. While group 1 was maintained on the same HFD (n=9), group 2 was switched to a normocholesterolemic diet (NCD; n=8) up to day 40. Blood was drawn at days 0 (baseline), 1, 3, 5, and 10 (to characterize HDL dysfunction over the 10-day period of dyslipidaemia induction), and at days 25 and 40 (to assess the HDL particle evolution in the intervention period). We assessed: a) HDL function [cholesterol efflux capacity (CEC) and antioxidant potential]; b) HDL particle number and size by nuclear magnetic resonance; c) oxidative susceptibility of LDL particles; d) HDL protein content of APOA-I, APOM, and APOC-III; and e) biochemical parameters.
 
 
 
 Up to day 10 there was a time-dependent increase in LDL-C levels that progressively induced the impairment of HDL CEC and antioxidant activity, higher HDL particle numbers, increased formation of conjugated dienes, and lower HDL-APOM content (p<0.01 vs baseline). All these parameters exhibited a plateau at day 10 and remained unchanged up to day 40 in those animals that were kept on HFD. Interestingly, in these animals a strong negative correlation was observed between HDL CEC and HDL-C levels (p<0.0001), with larger HDL particles being detected at day 40 (p<0.05 vs. baseline). On the contrary, all these parameters returned to physiological levels (baseline) in those animals that switched to a NCD (p=ns vs baseline). No changes were detected in APOA-I- and APOC-III- HDL content among animal groups and over time.
 
 
 
 In the present study we evidence for the first time that dyslipidaemia-induced HDL particle remodelling and dysfunction is not a permanent adverse change. The implementation of a healthy dietary intervention acutely reverses HDL adverse remodelling and dysfunction in a preclinical animal model.
