BackgroundSerum LDL-cholesterol (LDL-C) shows marked inter-individual variation in response to replacement of saturated fatty acids (SFA) with unsaturated fatty acids (UFA). ObjectiveTo 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. MethodsHealthy 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. ResultsTransition 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. ConclusionsThese 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 RegistryThe RISSCI-1 study was registered with ClinicalTrials.Gov (No. NCT03270527).