Angiopoietin-like 4 promotes the intracellular cleavage of lipoprotein lipase by PCSK3/furin in adipocytes

Dijk, Wieneke; Ruppert, Philip M.M.; Oost, Lynette J.; Kersten, Sander

doi:10.1074/jbc.ra118.002426

Cited by 53 publications

(56 citation statements)

References 52 publications

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“…It was previously proposed that ANGPTL4 inhibits LPL mainly in the subendothelial space, close to the site where both proteins are produced (40). Recent evidence suggests, however, that intracellular degradation of LPL may also be promoted by the ANGPTL4 protein (41,42). This makes ANGPTL4 an autocrine/paracrine regulator of LPL, which is unable to inactivate LPL when the enzyme has reached GPIHBP1 on the basal side of the capillary endothelium (10,37).…”

Section: Discussionmentioning

confidence: 99%

“…The low levels of ANGPTL4, still present in the cells, may form inactive complexes with ANGPTL8, whose expression is greatly increased (6,7,38). The ANGPTL4/ANGPTL8 complex may be unable to promote the intracellular degradation of LPL and thus allow more LPL to be secreted by WAT, but the precise mechanism for this process remains unclear (41,42). Because of the decreased levels of ANGPTL4 in the subendothelial space, LPL can reach GPIHBP1 and the luminal side of the capillaries and hydrolyze TGs from VLDLs and chylomicrons.…”

Section: Discussionmentioning

confidence: 99%

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On the mechanism of angiopoietin-like protein 8 for control of lipoprotein lipase activity

Kovrov

Kristensen

Larsson

et al. 2019

Journal of Lipid Research

102

148

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ANGPTL3, ANGPTL4, and ANGPTL8, are known to function as negative regulators of LPL activity in white adipose tissue (WAT), brown adipose tissue, and oxidative tissues (1-7). ANGPTL4, the most-studied family member, is expressed at various sites in the body (8). ANGPTL4 consists of an N-terminal coiled-coil domain (ccd) and a C-terminal, fibrinogen-like domain. The N-terminal ccd of ANGPTL4 inactivates LPL by promoting dissociation of the active LPL dimer into inactive monomers (9, 10). In this way, ANGPTL4 acts as a potent energy homeostasis switch causing reduced uptake of FAs from TG-rich lipoproteins in WAT during fasting (11,12). During physical activity or exercise, ANGPTL4 is upregulated in resting muscles, where it lowers LPL activity and thereby helps to direct FAs toward the contracting muscle tissue for energy production (13). In contrast to ANGPTL4, ANGPTL3 is mainly produced in the liver. It was previously demonstrated that the N-terminal ccd of ANGPTL3 reduces the activity of LPL in oxidative tissues in the fed state, thus directing the flow of lipoprotein-derived FAs to WAT for storage (14). In molar terms, ANGPTL3 is a relatively weak regulator of LPL in comparison to ANGPTL4 (10,15,16). Recent studies have shown, however, that the effect of ANGPTL3 on LPL is greatly enhanced by ANGPTL8 (15,17,18). ANGPTL8 is mostly produced in the liver and WAT and consists of a ccd, which is similar to those of ANGPTL3 and ANGPTL4, but ANGPTL8 is lacking a C-terminal, fibrinogen-like domain (6, 7). By itself, ANGPTL8 has no detectable effect on the activity of LPL. Reduction of LPL activity by ANGPTL8 occurs only in the presence of ANGPTL3 (15,18). It was recently demonstrated that ANGPTL8 needs to be coexpressed with ANGPTL3, by the same host cell, in order to have an effect on LPL activity (18).In this report, we show that recombinant ANGPTL8 produced in Escherichia coli has to be refolded together with Abstract Angiopoietin-like (ANGPTL) 8 is a secreted inhibitor of LPL, a key enzyme in plasma triglyceride metabolism. It was previously reported that ANGPTL8 requires another member of the ANGPTL family, ANGPTL3, to act on LPL. ANGPTL3, much like ANGPTL4, is a physiologically relevant regulator of LPL activity, which causes irreversible inactivation of the enzyme. Here, we show that ANGPTL8 can form complexes with either ANGPTL3 or ANGPTL4 when the proteins are refolded together from their denatured states. In contrast to the augmented inhibitory effect of the ANGPTL3/ ANGPTL8 complex on LPL activity, the ANGPTL4/ANGPTL8 complex is less active compared with ANGPTL4 alone. In our experiments, all three members of the ANGPTL family use the same mechanism to inactivate LPL, which involves dissociation of active dimeric LPL to monomers. This inactivation can be counteracted by the presence of glycosylphosphatidylinositol-anchored HDL binding protein 1, the endothelial LPL transport protein previously known to protect LPL from spontaneous and ANGPTL4-catalyzed inactivation. Our data demonstrate that ANGPTL8 may funct...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

On the mechanism of angiopoietin-like protein 8 for control of lipoprotein lipase activity

Kovrov

Kristensen

Larsson

et al. 2019

Journal of Lipid Research

102

148

View full text Add to dashboard Cite

show abstract

“…LPL is widely expressed in muscle and capillary endothelial cells in adipose tissue, and serves an important role in fat metabolism by catalyzing the breakdown of chylomicrons and low-density lipoproteins into glycerol and free fatty acids (23). Previous studies have demonstrated that insulin reduces chylomicron levels in the blood by enhancing the activity of LPL and inhibits hormone-sensitive lipase in lipocytes to decrease the breakdown of lipocytes and the production of TG (11).…”

Section: Discussionmentioning

confidence: 99%

Effects of different triglyceride‑lowering therapies in patients with hypertriglyceridemia‑induced acute pancreatitis

Yao

Xia

et al. 2020

Exp Ther Med

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The aim of the present study was to investigate the effects of various triglyceride (TG)-lowering therapies on hypertriglyceridemia-induced acute pancreatitis (HTGAP). A total of 132 patients with HTGAP were retrospectively divided into an insulin intensive therapy (IIT), a plasma exchange (PE) and a non-intensive insulin therapy (NIIT) group according to the TG-lowering therapies they had received. The clinical and biochemical data of the subjects were analyzed. The baseline data, including sex, age, TG, amylase, severe acute pancreatitis and systemic inflammatory response syndrome were not significantly different among the three groups (P>0.05). The 24-h TG clearance rate (χ 2 =7.74, P=0.021), onset to treatment time (χ 2 =14.50, P<0.001) and the time required to reach the target TG level (χ 2 =6.12, P=0.047) were different in these three groups, but no significant differences were observed between the IIT and NIIT groups (P>0.05). The incidence of therapy-associated complications in the PE group (30.23%) was higher than that in the IIT (2.17%) and NIIT (4.65%) groups. The difference in the incidence of therapy-associated complications was significant among the three groups (P<0.001), but no significant difference was present between the IIT and NIIT groups (P>0.05). In the PE group, the length of stay was increased compared with that in the IIT and NIIT groups (χ 2 =7.05, P<0.05), while there was no significant difference between the IIT and NIIT groups (P>0.05). The present study suggested that NIIT at presentation had a similar therapeutic efficacy to that of IIT to improve the prognosis of HTGAP, and NIIT and IIT were associated with fewer complications than PE treatment. NIIT may favorably perform in patients presenting early after symptom onset and may be considered for clinical application.

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“…Studies have shown that the Nterminal helix domain of ANGPTL4 can bind to LPL and change it from active dimers to form inactive monomers [33]. In addition, ANGPTL4 can also reduce the secretion of LPL in adipocytes [34][35][36].…”

Section: Interaction Between Angptl4 and Angptl8mentioning

confidence: 99%

Regulation of angiopoietin-like protein 8 expression under different nutritional and metabolic status

et al. 2019

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Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with increasing prevalence worldwide. Angiopoietin-like protein 8 (ANGPTL8), a member of the angiopoietin-like protein family, is involved in glucose metabolism, lipid metabolism, and energy homeostasis and believed to be associated with T2DM. Expression levels of ANGPTL8 are often significantly altered in metabolic diseases, such as non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus. Studies have shown that ANGPTL8, together with other members of this protein family, such as angiopoietin-like protein 3 (ANGPTL3) and angiopoietin-like protein 4 (ANGPTL4), regulates the activity of lipoprotein lipase (LPL), thereby participating in the regulation of triglyceride related lipoproteins (TRLs). In addition, members of the angiopoietin-like protein family are varyingly expressed among different tissues and respond differently under diverse nutritional and metabolic status. These findings may provide new options for the diagnosis and treatment of diabetes, metabolic syndromes and other diseases. In this review, the interaction between ANGPTL8 and ANGPTL3 or ANGPTL4, and the differential expression of ANGPTL8 responding to different nutritional and metabolic status during the regulation of LPL activity were reviewed.

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Angiopoietin-like 4 promotes the intracellular cleavage of lipoprotein lipase by PCSK3/furin in adipocytes

Cited by 53 publications

References 52 publications

On the mechanism of angiopoietin-like protein 8 for control of lipoprotein lipase activity

On the mechanism of angiopoietin-like protein 8 for control of lipoprotein lipase activity

Effects of different triglyceride‑lowering therapies in patients with hypertriglyceridemia‑induced acute pancreatitis

Regulation of angiopoietin-like protein 8 expression under different nutritional and metabolic status

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