Docosahexaenoic Acid Alters Lipid Metabolism Processes via H3K9ac Epigenetic Modification in Dairy Goat

Goat milk is increasingly recognized by consumers due
to its high
nutritional value, richness in short- and medium-chain fatty acids,
and richness in polyunsaturated fatty acids (PUFA). Exogenous supplementation
of docosahexaenoic acid (DHA) is an important approach to increasing
the content of PUFA in goat milk. Several studies have reported benefits
of dietary DHA in terms of human health, including potential against
chronic diseases and tumors. However, the mechanisms whereby an increased
supply of DHA regulates mammary cell function is unknown. In this
study, we investigated the effect of DHA on lipid metabolism processes
in goat mammary epithelial cells (GMEC) and the function of H3K9ac
epigenetic modifications in this process. Supplementation of DHA promoted
lipid droplet accumulation increased the DHA content and altered fatty
acid composition in GMEC. Lipid metabolism processes were altered
by DHA supplementation through transcriptional programs in GMEC. ChIP-seq
analysis revealed that DHA induced genome-wide H3K9ac epigenetic changes
in GMEC. Multiomics analyses (H3K9ac genome-wide screening and RNA-seq)
revealed that DHA-induced expression of lipid metabolism genes (FASN, SCD1, FADS1, FADS2, LPIN1, DGAT1, MBOAT2), which were closely related with changes in lipid
metabolism processes and fatty acid profiles, were regulated by modification
of H3K9ac. In particular, DHA increased the enrichment of H3K9ac in
the promoter region of PDK4 and promoted its transcription,
while PDK4 inhibited lipid synthesis and activated
AMPK signaling in GMEC. The activation of the expression of fatty
acid metabolism-related genes FASN, FADS2, and SCD1 and their upstream transcription factor SREBP1 by the AMPK inhibitor was attenuated in PDK4-overexpressing GMEC. In conclusion, DHA alters lipid metabolism
processes via H3K9ac modifications and the PDK4-AMPK-SREBP1 signaling
axis in goat mammary epithelial cells, providing new insights into
the mechanism through which DHA affects mammary cell function and
regulates milk fat metabolism.