FAM3A Inhibits Plasma Triglyceride Levels via Microvasculature-Involved Enhancement of VLDL-Triglyceride Hydrolysis and Lipid Uptake.
5 affiliations
- 1Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- 2Department of Computational Biology and Bioinformatics, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- 3Institute of Clinical Medicine, Center for Biomarker Discovery and Validation, National Infrastructure for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- 4State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- 5National Infrastructures for Translational Medicine, Institute of Clinical Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Abstract
FAM3 metabolism regulating signaling molecule A (FAM3A) is ubiquitously expressed. However, its biological role remains largely unknown. This study investigated the regulatory roles of FAM3A in plasma triglyceride (TG) levels. Proteomics revealed upregulated lipid metabolism-related proteins, including CD36 and TCF15, in skeletal muscle of FAM3A-transgenic mice. Clinically, plasma FAM3A was reduced in patients with metabolic disorders. FAM3A-transgenic mice and recombinant FAM3A (rcFAM3A) injection in mice significantly reduced plasma TG levels, upregulated tissue lipid uptake and lipid transporter expression in skeletal muscle. Microvascular endothelial cells (MVECs) from soleus and heart of FAM3A-transgenic mice or rcFAM3A-infused mice exhibited increased fatty acid (FA) uptake and trans-endothelial transport. Accordingly, FAM3A increased CD36 and TCF15 expression in MVECs derived from soleus, and increased CD36 expression was also observed in both C2C12 and MVECs treated by FAM3A in vitro. The siRNA-mediated knockdown of TCF15 or CD36 effectively inhibited FA uptake. Notably, FAM3A increased the luminal localization and activity of lipoprotein lipase (LPL) in endothelium, enhancing plasma VLDL-TG hydrolysis both in vivo and in vitro. However, FAM3A showed no effect on hepatic VLDL production or intestinal lipid absorption. Importantly, FAM3A exerted these effects primarily by activating PPARα signaling, as pharmacological blockage of PPARα with GW6471 inhibited FAM3A-induced upregulation of CD36 and TCF15 expression, endothelial lumen LPL localization and activity, FA uptake and trans-endothelial transport, and plasma TG clearance. Collectively, these findings reveal a pivotal role of FAM3A in plasma TG catabolism, identifying that the FAM3A/PPARα axis drives LPL-mediated TG lipolysis, lipid-transendothelial delivery, and tissue FA uptake.
Related
- Retinal microvasculature alterations are associated with mild behavioral impairment in Southeast Asian dementia-free older adults.
- Loss of stromal VEGFR2 protects against ischemic acute kidney injury by preserving the renal microvasculature
- Retinal arteriolar tortuosity as a candidate genetic window to inner-ear microvasculature: distributed sharing with blood pressure at CSK and PAWR and a roadmap for larger hearing GWAS
- E-cigarette aerosols induce the hydrolysis of lysosomal glycerophospholipids through PLA2G4A activation initiated by nicotine binding to CHRNA3/α3 nAChR in airway epithelial cells
- Association of the triglyceride-glucose index and triglyceride-glucose-body mass index with postoperative atrial fibrillation in patients undergoing off-pump coronary artery bypass grafting: a retrospective cohort study
BibTeX
@article{song2026fam3a,
title = {{FAM3A Inhibits Plasma Triglyceride Levels via Microvasculature-Involved Enhancement of VLDL-Triglyceride Hydrolysis and Lipid Uptake.}},
author = {Xiaohong Song and Wenxuan Xiang and Xiangyu Xian and Lichai Yuan and Jianqiang Wu and Bintao Qiu and Dan Yang and Yuehong Zheng},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
year = {2026},
month = oct,
doi = {10.1096/fj.202602574r},
url = {https://europepmc.org/article/MED/42876221},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - FAM3A Inhibits Plasma Triglyceride Levels via Microvasculature-Involved Enhancement of VLDL-Triglyceride Hydrolysis and Lipid Uptake.
AU - Xiaohong Song
AU - Wenxuan Xiang
AU - Xiangyu Xian
AU - Lichai Yuan
AU - Jianqiang Wu
AU - Bintao Qiu
AU - Dan Yang
AU - Yuehong Zheng
PY - 2026
DA - 2026/10/01
JO - FASEB journal : official publication of the Federation of American Societies for Experimental Biology
DO - 10.1096/fj.202602574r
UR - https://europepmc.org/article/MED/42876221
AB - FAM3 metabolism regulating signaling molecule A (FAM3A) is ubiquitously expressed. However, its biological role remains largely unknown. This study investigated the regulatory roles of FAM3A in plasma triglyceride (TG) levels. Proteomics revealed upregulated lipid metabolism-related proteins, including CD36 and TCF15, in skeletal muscle of FAM3A-transgenic mice. Clinically, plasma FAM3A was reduced in patients with metabolic disorders. FAM3A-transgenic mice and recombinant FAM3A (rcFAM3A) injection in mice significantly reduced plasma TG levels, upregulated tissue lipid uptake and lipid transporter expression in skeletal muscle. Microvascular endothelial cells (MVECs) from soleus and heart of FAM3A-transgenic mice or rcFAM3A-infused mice exhibited increased fatty acid (FA) uptake and trans-endothelial transport. Accordingly, FAM3A increased CD36 and TCF15 expression in MVECs derived from soleus, and increased CD36 expression was also observed in both C2C12 and MVECs treated by FAM3A in vitro. The siRNA-mediated knockdown of TCF15 or CD36 effectively inhibited FA uptake. Notably, FAM3A increased the luminal localization and activity of lipoprotein lipase (LPL) in endothelium, enhancing plasma VLDL-TG hydrolysis both in vivo and in vitro. However, FAM3A showed no effect on hepatic VLDL production or intestinal lipid absorption. Importantly, FAM3A exerted these effects primarily by activating PPARα signaling, as pharmacological blockage of PPARα with GW6471 inhibited FAM3A-induced upregulation of CD36 and TCF15 expression, endothelial lumen LPL localization and activity, FA uptake and trans-endothelial transport, and plasma TG clearance. Collectively, these findings reveal a pivotal role of FAM3A in plasma TG catabolism, identifying that the FAM3A/PPARα axis drives LPL-mediated TG lipolysis, lipid-transendothelial delivery, and tissue FA uptake.
SN - 0892-6638
SN - 1530-6860
ER -