Abstract/Summary

Background: Serum LDL-cholesterol (LDL-C) shows marked inter-individual variation in response to replacement of saturated fatty acids (SFA) with unsaturated fatty acids (UFA). Objective: To demonstrate the efficacy of UK guidelines for exchanging dietary SFA for UFA, to reduce serum LDL-C and other CVD risk factors, and to identify determinants of the variability in LDL-C response. Methods: Healthy males (n=109, mean±SD age 48±11 years BMI 25.1±3.3 kg/m2), consumed a higher-SFA/lower-UFA diet for 4-weeks, followed by an isoenergetic, lower-SFA/higher-UFA diet for 4-weeks (achieved intakes SFA:UFA, 19.1:14.8 and 8.9:24.5% total energy respectively). Serum LDL-C, CVD risk markers, peripheral blood mononuclear cell (PBMC) gene expression, and dietary intakes were assessed at baseline and the end of each diet. Results: Transition from a higher-SFA/lower-UFA to a lower-SFA/higher-UFA diet significantly reduced fasting blood lipids [LDL-C (-0.50 mmol/L; 95%CI:-0.58,-0.42), HDL-C (-0.11 mmol/L; 95%CI:-0.14,-0.08) and total cholesterol (-0.65 mmol/L; 95%CI:-0.75,-0.55)]. The dietary exchange also reduced apolipoprotein (apo)B, TC:HDL-C ratio, non-HDL-C, E-selectin (P<0.0001) and LDL subfraction composition [cholesterol (LDL-I and LDL-II), apoB100 (LDL-I and LDL-II), and TAG (LDL-II)] (P<0.01). There was also an increase in plasma biomarkers of cholesterol intestinal absorption (β-sitosterol, campesterol, cholestanol), and synthesis (desmosterol) (P<0.0001) and fold change in PBMC LDL-receptor mRNA expression relative to the higher-SFA/lower-UFA diet (P=0.035). Marked inter-individual variation in the change in serum LDL-C response (-1.39 to +0.77 mmol/L) to this dietary exchange was observed, with 33.7% of this variation explained by serum LDL-C before the lower-SFA/higher-UFA diet and reduction in dietary SFA intake (adjusted R2 27% and 6.7%, respectively). APOE genotype was unrelated to serum LDL-C response to SFA. Conclusions: These findings support the efficacy of UK SFA dietary guidelines for the overall lowering of serum LDL-C, but showed marked variation in LDL-C response. Further identification of the determinants of this variation will facilitate targeting and increasing efficacy of these guidelines. Clinical trial registry: The RISSCI-1 study was registered with ClinicalTrials.Gov (No. NCT03270527).