Methods and results

Experiments were carried out in mice fed a low‐fat, low‐cholesterol (LFLC) diet, an HFHC‐SFA diet or an HFHC‐PUFA diet in which SFAs were partly replaced with an alternative high‐linoleic and α‐linolenic fat source. The HFHC‐SFA caused a significant increase in serum HDL cholesterol and phospholipids as well as elevated levels of oxidized HDL and oxidized LDL. Replacing SFA with PUFA significantly reduced the levels of these oxidized lipoproteins and enhanced the ability of HDL to protect LDL from oxidation. The SFA‐mediated impairment of HDL antioxidant potential was not associated with the cholesterol content of the diet, obesity or insulin resistance. In contrast, the effect of the HFHC diets on fecal macrophage‐derived cholesterol excretion was independent of the fatty acid source.