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bioRxiv · 10.1101/2025.11.15.685896

DHA Increases Angptl4 Gene Expression and Reduces LPL Activity in a PPARγ-dependent manner in Adipocytes

McTavish, P. V.·Rajna, A.·Brown, L. H.·Elzaanoun, R.·Mutch, D. M.
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Abstract

Omega-3 polyunsaturated fatty acids (N-3 PUFA), specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are well recognized for their triacylglycerol (TAG)-lowering properties. These effects are generally attributed to reduced hepatic lipogenesis and increased {beta}-oxidation; however, the contribution of white adipose tissue (WAT) towards the hypotriglyceridemic properties of N-3 PUFA is less defined. Lipoprotein lipase (LPL) regulates TAG hydrolysis to influence fatty acid uptake into WAT, a process that can be inhibited by angiopoietin-like 4 (ANGPTL4). When re-examining a previous mouse study, we found that mice consuming a diet rich in EPA/DHA had increased WAT Angptl4 expression in the fasted state compared to a control diet. Therefore, the goal of this study was to explore the role of N-3 PUFA on the regulation of Angptl4 expression and LPL activity in mouse adipocytes. 3T3-L1 adipocytes treated with DHA (100M), but not ALA or EPA, increased Angptl4 expression and reduced LPL activity similar to that observed with a PPAR{gamma} agonist (pioglitazone). When Ppar{gamma} expression was knocked down with siRNA, the ability of DHA and pioglitazone to induce Angptl4 expression was ablated. Further, DHA- and pioglitazone-induced reductions in LPL activity were mitigated when Angptl4 expression was silenced. Taken together, these results suggest that DHA regulates LPL activity by increasing Angptl4 expression in a PPAR{gamma}-dependent manner. Our results have uncovered a novel mechanism by which DHA regulates ANGPTL4 to influence LPL-mediated hydrolysis of circulating TAG in adipocytes. Future in-vivo studies are necessary to determine the relevance of DHA regulation of ANGPTL4 towards whole-body lipid homeostasis and cardiometabolic health. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/685896v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@75505dorg.highwire.dtl.DTLVardef@1ef29b4org.highwire.dtl.DTLVardef@9aec7dorg.highwire.dtl.DTLVardef@11c372b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDHA increases Angptl4 gene expression and reduces LPL activity in 3T3-L1 adipocytes C_LIO_LIChanges in FOXO1 do not explain DHA-induced changes in Angptl4 gene expression C_LIO_LISilencing Ppar{gamma} ablates DHA-induced increases in Angptl4 gene expression C_LIO_LISilencing Angptl4 partially attenuates DHA-induced reductions in LPL activity C_LI

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McTavish, P. V., Rajna, A., Brown, L. H., Elzaanoun, R., Mutch, D. M.. 2025-11-16. DHA Increases Angptl4 Gene Expression and Reduces LPL Activity in a PPARγ-dependent manner in Adipocytes. https://doi.org/10.1101/2025.11.15.685896

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