Intracapillary LPL levels in brown adipose tissue, visualized with an antibody-based approach, are regulated by ANGPTL4 at thermoneutral temperatures.
Intracapillary LPL levels in brown adipose tissue, visualized with an antibody-based approach, are regulated by ANGPTL4 at thermoneutral temperatures.
复制标题
DOI：
10.1073/pnas.2219833120
复制
发表时间：
2023-02-21
影响因子：
11.1
通讯作者：
Fong, Loren G.
中科院分区：
文献类型：
--
作者：
Song, Wenxin;Yang, Ye;Heizer, Patrick;Tu, Yiping;Weston, Thomas A.;Kim, Joonyoung R.;Munguia, Priscilla;Jung, Hyesoo;Fong, Jared L. -C.;Tran, Caitlyn;Ploug, Michael;Beigneux, Anne P.;Young, Stephen G.;Fong, Loren G.
Lipoprotein lipase (LPL), an intravascular triglyceride hydrolase, is crucial for plasma triglyceride metabolism, and genetic variation that reduces LPL-mediated triglyceride hydrolysis increases the risk of coronary heart disease. Intravascular LPL levels are frequently inferred from measurements of triglyceride hydrolase activity in the plasma after a bolus of heparin, but whether such measurements truly reflect intravascular LPL levels has been unclear. We developed a direct, antibody-based method to both visualize and quantify intravascular LPL levels. We discovered that LPL levels in capillaries fall sharply in brown adipose tissue (but not heart) under thermoneutral conditions, due to increased ANGPTL4 expression. Our methods can be applied to define the impact of genetic variation, hypolipidemic drugs, and metabolic diseases on intravascular LPL levels. Lipoprotein lipase (LPL) is secreted into the interstitial spaces by parenchymal cells and then transported into capillaries by GPIHBP1. LPL carries out the lipolytic processing of triglyceride (TG)-rich lipoproteins (TRLs), but the tissue-specific regulation of LPL is incompletely understood. Plasma levels of TG hydrolase activity after heparin injection are often used to draw inferences about intravascular LPL levels, but the validity of these inferences is unclear. Moreover, plasma TG hydrolase activity levels are not helpful for understanding LPL regulation in specific tissues. Here, we sought to elucidate LPL regulation under thermoneutral conditions (30 °C). To pursue this objective, we developed an antibody-based method to quantify (in a direct fashion) LPL levels inside capillaries. At 30 °C, intracapillary LPL levels fell sharply in brown adipose tissue (BAT) but not heart. The reduced intracapillary LPL levels were accompanied by reduced margination of TRLs along capillaries. ANGPTL4 expression in BAT increased fourfold at 30 °C, suggesting a potential explanation for the lower intracapillary LPL levels. Consistent with that idea, Angptl4 deficiency normalized both LPL levels and TRL margination in BAT at 30 °C. In Gpihbp1–/– mice housed at 30 °C, we observed an ANGPTL4-dependent decrease in LPL levels within the interstitial spaces of BAT, providing in vivo proof that ANGPTL4 regulates LPL levels before LPL transport into capillaries. In conclusion, our studies have illuminated intracapillary LPL regulation under thermoneutral conditions. Our approaches will be useful for defining the impact of genetic variation and metabolic disease on intracapillary LPL levels and TRL processing.
登录
查看更多内容
影响因子：
29
作者：
Goulbourne CN;Gin P;Tatar A;Nobumori C;Hoenger A;Jiang H;Grovenor CR;Adeyo O;Esko JD;Goldberg IJ;Reue K;Tontonoz P;Bensadoun A;Beigneux AP;Young SG;Fong LG
通讯作者：
Fong LG
DOI：
10.1073/pnas.2026650118
发表时间：
2021-03-23
影响因子：
11.1
作者：
Leth-Espensen, Katrine Z.;Kristensen, Kristian K.;Ploug, Michael
通讯作者：
Ploug, Michael
DOI：
10.1161/atvbaha.109.186577
发表时间：
2009-06
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Beigneux AP;Franssen R;Bensadoun A;Gin P;Melford K;Peter J;Walzem RL;Weinstein MM;Davies BS;Kuivenhoven JA;Kastelein JJ;Fong LG;Dallinga-Thie GM;Young SG
通讯作者：
Young SG
影响因子：
15.9
作者：
HAVEL, RJ;GORDON, RS
通讯作者：
GORDON, RS
影响因子：
7.7
作者：
Mysling, Simon;Kristensen, Kristian Kolby;Ploug, Michael
通讯作者：
Ploug, Michael