Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids

Abstract

Angiopoietin-like protein 8 (ANGPTL8) has been implicated in metabolic syndrome and reported to regulate adipose FA uptake through unknown mechanisms. Here, we studied how complex formation of ANGPTL8 with ANGPTL3 or ANGPTL4 varies with feeding to regulate lipoprotein lipase (LPL). In human serum, ANGPTL3/8 and ANGPTL4/8 complexes both increased postprandially, correlated negatively with HDL, and correlated positively with all other metabolic syndrome markers. ANGPTL3/8 also correlated positively with LDL-cholesterol and blocked LPL-facilitated hepatocyte VLDL-cholesterol uptake. LPL-inhibitory activity of ANGPTL3/8 was >100-fold more potent than that of ANGPTL3, and LPL-inhibitory activity of ANGPTL4/8 was >100-fold less potent than that of ANGPTL4. Quantitative analyses of inhibitory activities and competition experiments among the complexes suggested a model in which localized ANGPTL4/8 blocks the LPL-inhibitory activity of both circulating ANGPTL3/8 and localized ANGPTL4, allowing lipid sequestration into fat rather than muscle during the fed state. Supporting this model, insulin increased ANGPTL3/8 secretion from hepatocytes and ANGPTL4/8 secretion from adipocytes. These results suggest that low ANGPTL8 levels during fasting enable ANGPTL4-mediated LPL inhibition in fat tissue to minimize adipose FA uptake. During feeding, increased ANGPTL8 increases ANGPTL3 inhibition of LPL in muscle via circulating ANGPTL3/8, while decreasing ANGPTL4 inhibition of LPL in adipose tissue through localized ANGPTL4/8, thereby increasing FA uptake into adipose tissue. Excessive caloric intake may shift this system toward the latter conditions, possibly predisposing to metabolic syndrome.

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

“…Importantly, several exchangeable apolipoproteins modulate LPL activity, including ApoC2 and ApoA5, which stimulate LPL activity, and ApoC1, ApoC3, and ApoE, which inhibit LPL activity. Additionally, angiopoietin-like proteins ANGPTL3 and ANGPTL4 also inhibit LPL individually, particularly when complexed with ANGPTL8 [ 75 ].…”

The Interplay between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship between Adiposopathy and Cardiometabolic Diseases?

“…While liver-derived ANGPTL8 is largely secreted in plasma, produced by adipocytes, remains intracellularly, particularly localized in nucleoplasm [ 67 , 68 , 69 ]. It is a small protein of 198 residues, capable of interaction with ANGPTL3, but exposing a coiled-coil domain only [ 7 , 70 ]. It is induced by feeding and facilitates the LPL inhibition activity by forming oligomers with ANGPTL3 [ 7 , 70 ].…”

“…It is a small protein of 198 residues, capable of interaction with ANGPTL3, but exposing a coiled-coil domain only [ 7 , 70 ]. It is induced by feeding and facilitates the LPL inhibition activity by forming oligomers with ANGPTL3 [ 7 , 70 ]. It was recently proved that insulin acts as a powerful inducer of ANGPTL8 via PI3K/AKT signaling [ 68 , 71 , 72 ], and insulin-dependent ANGPTL8 induction occurs similarly in the liver and adipose tissue [ 68 ].…”

“…Chen et al [ 70 ], found that ANGPTL8 is able to form complexes with both ANGPTL3 (in a 3:1 molar ratio) and ANGPTL4 (in 1:1 molar ratio) [ 70 ]. ANGPTL3/8 complexes are 100-times more potent in LPL inhibition than ANGPTL4/8 complexes, thus establishing a possible competitive mechanism in regulating LPL-activity in different tissues [ 70 ]…”

“…While hepatocyte-derived ANGPTL8 is mainly secreted, in WAT and BAT it remains in nucleoplasm [ 69 ]. According to this model, ANGPTL8 is secreted in complexes with ANGPTL3, thus inhibiting LPL in oxidative tissues and directing dietary TGs to adipose tissue for storage [ 7 , 70 ]. Enhanced ANGPTL8 is associated with reduced activation of AMPK and PPARα inhibition (that regulates ANGPTL4 expression) [ 92 , 93 ].…”