Tissue-specific regulation of PNPLA3 promotes lipid remodeling in response to dietary and temperature stress

Wu, P.; Wang, Y.; Cohen, J. C.; Hobbs, H. H.

doi:10.1101/2025.10.27.684800

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bioRxiv · 10.1101/2025.10.27.684800

Tissue-specific regulation of PNPLA3 promotes lipid remodeling in response to dietary and temperature stress

Wu, P.·Wang, Y.·Cohen, J. C.·Hobbs, H. H.

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Abstract

Background & AimsPNPLA3(I148M) is the strongest genetic risk factor for steatotic liver disease (SLD), but its functional role and tissue-specific regulation remain unclear. In mice, PNPLA3 is abundant in liver, yet undetectable in adipose depots. Here, we characterize the molecular mechanisms underlying these tissue-specific differences in PNPLA3 expression in mice to clarify its functional role and link to SLD risk. MethodsPnpla3 mRNA and PNPLA3 protein levels were quantified in liver and adipose depots of fasted and refed mice at 30{degrees}C and 6{degrees}C. Signaling pathways regulating PNPLA3 expression in adipocytes were examined using adrenergic agonists and pathway-specific modulators. Translation and proteasomal inhibitors were used during adrenergic stimulation to investigate the discordance between Pnpla3 mRNA and protein levels. Relationship between PNPLA3 levels and triglyceride (TG) fatty acid composition was also assessed. ResultsAt thermoneutrality, feeding strongly increased PNPLA3 levels in liver but it remained undetectable in adipose tissue of mice. Conversely, cold exposure or {beta}3-adrenergic stimulation had no effect on hepatic PNPLA3, but increased PNPLA3 >19-fold in brown adipose tissue (BAT), despite causing a >75% reduction in Pnpla3 mRNA, indicating robust post-translational regulation. In BAT, adrenergic signaling via cAMP/PKA and PI3K/AKT elevated PNPLA3 by reducing proteasomal degradation. PNPLA3 expression correlated with depletion of TG-long-chain polyunsaturated fatty acids (TG-LCPUFAs) in both liver and BAT, consistent with a role in lipid remodeling. ConclusionsThese findings reveal striking tissue- and context-specific regulation of PNPLA3, but a conserved association between its expression and TG-LCPUFAs levels, suggesting that PNPLA3 modulates lipid remodeling in response to metabolic stress and that disrupting this function may contribute to SLD susceptibility. Impact and implicationsDespite being the strongest genetic risk factor for SLD, PNPLA3s physiological role remains unclear. Using mouse models, this study reveals that PNPLA3 is regulated in a tissue-specific manner in response to feeding and cold exposure, thereby promoting remodeling of cellular lipids to adapt to dietary and environmental challenges. The localization of PNPLA3 action and its tissue-specific regulation are directly relevant to hepatologists and metabolic researchers aiming to understand its influence on intracellular lipid composition and its effects on disease susceptibility. Moreover, modulation of PNPLA3 turnover--and its impact on LCPUFAs remodeling--emerges as a potential therapeutic strategy for regulating lipid homeostasis in SLD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=191 SRC="FIGDIR/small/684800v2_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@ee6ac7org.highwire.dtl.DTLVardef@a45d74org.highwire.dtl.DTLVardef@f39929org.highwire.dtl.DTLVardef@cc826b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPNPLA3 is regulated in a highly tissue-specific manner in mice. C_LIO_LIIn liver, feeding-but not cold exposure-induces PNPLA3 primarily through transcriptional mechanisms. C_LIO_LIIn adipose tissue, cold exposure-but not feeding-induces PNPLA3 through post-transcriptional mechanisms. C_LIO_LIIn adipose tissue, cold exposure increases PNPLA3 despite a reduction in Pnpla3 mRNA. C_LIO_LIPNPLA3 remodels lipids in liver and adipose tissue to maintain lipid homeostasis, a process disrupted in SLD. C_LI

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Wu, P., Wang, Y., Cohen, J. C., Hobbs, H. H.. 2025-10-27. Tissue-specific regulation of PNPLA3 promotes lipid remodeling in response to dietary and temperature stress. https://doi.org/10.1101/2025.10.27.684800

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