Sn-2 palmitate ameliorates dyslipidemia in high-fat-fed aged mice via bile acid-mediated gut-liver-adipose cross-talk

A 6-month intervention in aged male C57BL/6J mice suggested that dietary sn-2 palmitate-enriched triacylglycerols (sn-2 PTAG) dose-dependently ameliorated high-fat diet-induced metabolic deterioration. The higher sn-2 PTAG doses (59.15% and 75.79%) significantly reduced liver weight, hepatic steatosis, adipocyte hypertrophy, serum total cholesterol and LDL-c levels. Mechanistically, sn-2 PTAG enhanced intestinal fatty acid absorption via upregulating transporters CD36 and FATP4, while suppressing hepatic de novo lipogenesis through downregulation of the key transcription factor SREBP-1c. Concurrently, it stimulated adipose tissue remodeling, characterized by the activation of lipolysis through elevated ATGL and the induction of thermogenesis via upregulation of PGC1α and UCP1. Crucially, sn-2 PTAG reshaped bile acid metabolism by enhancing hepatic synthesis, as evidenced by the upregulation of CYP7A1 and CYP8B1, which led to elevated levels of cholic acid and its taurine-conjugated form, taurocholic acid. This was accompanied by an altered intestinal bile acid profile, marked by increased concentrations of taurocholic acid and deoxycholic acid. These metabolic shifts were paralleled by reduced levels of FXR and FGF15, and increased level of TGR5, which may be associated with suppression of the FXR-FGF15 axis and activation of TGR5 signaling. Collectively, sn-2 PTAG may contribute to the regulation of the bile acid-mediated gut-liver-adipose axis, which is associated with dual modulation of cholesterol clearance and energy dissipation pathways, thereby offering a potential structural lipid-based strategy against age-related dyslipidemia. Our findings provided a scientific basis for developing structured dietary lipids as functional foods against age-related metabolic syndrome.