Regulation of plasma triglyceride partitioning by adipose-derived ANGPTL4 in mice

Abstract

Elevated plasma triglyceride levels are associated with metabolic disease. Angiopoietin-like protein 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). Our aim was to investigate the role of adipocyte-specific deficiency of ANGPTL4 in mice during high fat diet feeding. Adipocyte-specific ANGPTL4 deficient mice were fed a high fat diet (60% kCal from fat) for either 12 weeks or 6 months. We performed plasma metabolic measurements, triglyceride clearance and uptake assays, LPL activity assays, and assessed glucose homeostasis. Mice lacking adipocyte ANGPTL4 recapitulated the triglyceride phenotypes of whole-body ANGPTL4 deficiency, including increased adipose LPL activity, lower plasma triglyceride levels, and increased uptake of triglycerides into adipose tissue. When fed a high fat diet (HFD), these mice continued to display enhanced adipose LPL activity and initially had improved glucose and insulin sensitivity. However, after 6 months on HFD, the improvements in glucose homeostasis were largely lost. Moreover, despite higher adipose LPL activity levels, mice lacking adipocyte ANGPTL4 no longer had increased triglyceride uptake into adipose compared to littermate controls after chronic high-fat feeding. These observations suggest that after chronic high-fat feeding LPL is no longer rate-limiting for triglyceride delivery to adipocytes. We conclude that while adipocyte-derived ANGPTL4 is an important regulator of plasma triglyceride levels and triglyceride partitioning under normal diet conditions, its role is diminished after chronic high-fat feeding.

Extracellular vesicle release and uptake by the liver under normo- and hyperlipidemia

“…The ACD tubes were used to prevent in vitro vesiculation [ 20 ]. The blood samples were spun once at 1500× g for 15 min [ 21 ]. Based on the protein and particle content, protein/particle ratio, EV and non-EV markers, we found that the number of centrifugations in plasma isolation protocol did not affect the EV content (Supplementary Fig.…”

Role and mechanism of the action of angiopoietin-like protein ANGPTL4 in plasma lipid metabolism

“…Conversely, whole-body inactivation or partial inactivation of ANGPTL4 decreases plasma TG levels, increases adipose tissue LPL activity, enhances the clearance of plasma TG, and enhances uptake of plasma TG-derived fatty acids into adipose tissue, which again is especially observed in the fasted but not the fed state ( 39 , 40 , 41 , 42 , 43 ). Studies in adipocyte-specific ANGPTL4-deficient mice underscore the suppressive effect of adipocyte-derived ANGPTL4 on adipose LPL activity and plasma TG clearance ( 44 ). The increase in adipose LPL activity in ANGPTL4-deficient mice is accompanied by an increase in adipose LPL mass, representing the EndonucleaseH-resistant LPL within the Golgi/postGolgi, and a decrease in the N-terminal LPL fragment ( 43 , 45 , 46 ).…”

“…Genetic support for the notion that ANGPTL4 specifically regulates plasma TG in the fasted state is provided by data showing that carrier status of a truncation variant of ANGPTL4 was only associated with lower plasma TG when individuals were fasted for at least 4 h ( 23 ). Collectively, it is evident that induction of ANGPTL4 mediates the decrease in LPL content and activity in adipose tissue during fasting, thereby partitioning circulating TG to other tissues ( 44 ).…”

Triglyceride and Triglyceride-Rich Lipoproteins in Atherosclerosis

“…This antibody also reduces plasma levels of TG in LDLR (−/−) , apoE (−/−) , and db/db mice ( Desai et al, 2007 ). Adipocyte-derived ANGPTL4 plays a key role in regulation of plasma TG in mice fed a regular chow diet, but this effect is diminished after a chronic high-fat diet feeding ( Spitler et al, 2021 ). Of importance, clinical trials are needed for determining the actual effects of inhibiting ANGPTL4 on TG-lowering.…”