bioRxiv Science⌕ Search
Home/Archive/bioRxiv

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.
View original source ↗Export metadata ↓

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

Explore related subjects

cell biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

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

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Sequence context and partner availability specify divergent cell fates from a single transcription factor

Transcription factors drive the gene regulatory networks that control developmental transitions, yet which of their many targets a cell uses remains unresolved. Expressing Cebp, Cebp{beta} or Cebp{delta} identically, alone or with Oct4, Sox2, Klf4 and cMyc, gave four outcomes: adipocyte from fibroblasts and neural stem cells, trophectoderm from embryonic stem cells, and myeloid from B cells. Raising Cebp levels changed how many sites it reached, not which sequence it read: clustered motifs maintained somatic enhancers, while spillover onto low-copy sites created de novo enhancers carrying composites of Cebp and cell-type-restricted partners. In fibroblasts, Cebp also redistributed Oct4, Sox2 and Klf4 from early targets, blocking iPSC formation. Supplying the predicted partners rewrote the output: Spi1 redirected Cebp into parallel adipogenic and myeloid programs, via a transient PpargCD45 state using separate enhancers for each; TFAP2C abolished adipogenic conversion. Motif density and partner composites therefore assemble a factor's instructive output in the receiving cell.

cell biology↗
bioRxiv2026

Tracking the conformational dynamics of single molecules in live cells; GTPase cycling in Cdc42 gradients and microclusters

The Rho family of GTPases play a critical role in many cellular processes by acting as molecular switches relying on conformational changes to transition between active and inactive states. The spatial distribution and kinetics of these conformational changes are complex and vary across the cell. We describe here biosensors based on environment-responsive fluorescent dyes, capable of reporting the conformational changes of individual GTPase molecules as they traffic within living cells (SPARC Cdc42 and SPARC Rac1, 'Single Particle Activation Reporter Constructs'). We use SPARC Cdc42 to determine the rates of different steps in GTPase regulation, activation/inactivation and membrane insertion, that together generate localized gradients of Cdc42 activity driving cell motility. The biosensors also revealed heterogeneously distributed clusters of Cdc42, the mechanisms of their activation, and potential roles in polarized motility.

cell biology↗
bioRxiv2026

High-content screening identifies FDA-approved activators of mitophagy

Mitochondrial diseases are highly heterogeneous disorders caused by defects in oxidative phosphorylation, for which only limited therapeutic options are available. The elimination of dysfunctional mitochondria via mitophagy activation is an attractive strategy to treat several mitochondrial diseases, irrespective of the underlying genetic defect. To identify pharmacological activators of this pathway, we performed a high-content screening of 1,971 FDA-approved compounds using cellular reporters of TFEB nuclear translocation and mitophagy. This screening identified 294 compounds that promoted TFEB translocation, nine of which increased the number of mitolysosomes without compromising cell viability or damaging mitochondria. Among the selected compounds, Meptazinol and Ponatinib emerged as the top-ranked mitophagy inducers in fibroblasts from patients with complex I and IV deficiency, respectively, and were prioritised for further characterisation. However, they did not rescue the bioenergetic defect, suggesting that the stimulation of mitophagy per se is not sufficient to ameliorate the OXPHOS defect in mitochondrial diseases. Overall, our findings establish a scalable platform for the identification of pharmacological activators of TFEB and identify candidate compounds for therapeutic modulation of mitophagy.

cell biology↗