ApoA5 lowers triglyceride levels via suppression of ANGPTL3/8-mediated LPL inhibition

Chen, Yanqun; Pottanat, Thomas G.; Zhen, Yuejun; Siegel, Robert W.; Ehsani, Mariam; Qian, Yue‐Wei; Konrad, Robert J.

doi:10.1016/j.jlr.2021.100068

Cited by 55 publications

(82 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given (i) that the ANGPTL3-ANGPTL8 complex is the relevant inhibitor of LPL; (ii) that ANGPTL3 and ANGPTL8 both are synthesized in the liver; and (iii) that ANGPTL8 expression is induced by feeding outlined a mechanism for differential regulation of TRL processing in different tissues dependent on nutritional cues (Figure 4A). An additional layer of complexity to the regulation of LPL activity was recently added by the finding that ApoA5 bound tightly to the ANGPTL3-ANGPTL8 complex in vitro and in vivo and this binding impaired the capacity of the complex to inhibit LPL (Chen et al, 2021).…”

Section: Angptl3 Forms An Lpl Inhibitory Complex With Angptl8mentioning

confidence: 99%

GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity

Kristensen

Leth-Espensen

Kumari

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Intravascular processing of triglyceride-rich lipoproteins (TRLs) is crucial for delivery of dietary lipids fueling energy metabolism in heart and skeletal muscle and for storage in white adipose tissue. During the last decade, mechanisms underlying focal lipolytic processing of TRLs along the luminal surface of capillaries have been clarified by fresh insights into the functions of lipoprotein lipase (LPL); LPL’s dedicated transporter protein, glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1); and its endogenous inhibitors, angiopoietin-like (ANGPTL) proteins 3, 4, and 8. Key discoveries in LPL biology include solving the crystal structure of LPL, showing LPL is catalytically active as a monomer rather than as a homodimer, and that the borderline stability of LPL’s hydrolase domain is crucial for the regulation of LPL activity. Another key discovery was understanding how ANGPTL4 regulates LPL activity. The binding of ANGPTL4 to LPL sequences adjacent to the catalytic cavity triggers cooperative and sequential unfolding of LPL’s hydrolase domain resulting in irreversible collapse of the catalytic cavity and loss of LPL activity. Recent studies have highlighted the importance of the ANGPTL3–ANGPTL8 complex for endocrine regulation of LPL activity in oxidative organs (e.g., heart, skeletal muscle, brown adipose tissue), but the molecular mechanisms have not been fully defined. New insights have also been gained into LPL–GPIHBP1 interactions and how GPIHBP1 moves LPL to its site of action in the capillary lumen. GPIHBP1 is an atypical member of the LU (Ly6/uPAR) domain protein superfamily, containing an intrinsically disordered and highly acidic N-terminal extension and a disulfide bond–rich three-fingered LU domain. Both the disordered acidic domain and the folded LU domain are crucial for the stability and transport of LPL, and for modulating its susceptibility to ANGPTL4-mediated unfolding. This review focuses on recent advances in the biology and biochemistry of crucial proteins for intravascular lipolysis.

show abstract

Section: Angptl3 Forms An Lpl Inhibitory Complex With Angptl8mentioning

confidence: 99%

GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity

Kristensen

Leth-Espensen

Kumari

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…In mice, there have been studies implicating a role of GM or its metabolites in regulating LPL function [ 59 ]. LPL function is further regulated by adipokines and other signaling molecules such as angiopoietin-like proteins (ANGPTLs) [ 82 ] and apolipoproteins including Apo-A5 [ 83 ], and there are findings that the gut microbiota and its metabolites influence these and in such a way regulate LPL-mediated lipolysis, causing shifts in triglyceride (TG) trafficking and subsequent dyslipidemia, as is summarized in Figure 2 A.…”

Section: Gut-microbiota-derived Metabolites In Dyslipidemia and Obesitymentioning

confidence: 99%

“…Apo-A5 is known to decrease plasma TG levels as certain variants of the APOA5 gene have been associated with hypertriglyceridemia [ 101 ]. Although the main mechanism of Apo-A5 appears to be its ability to regulate LPL, other modes of action have been proposed such as reducing VLDL release by the liver, enhancing uptake of TG-containing particles, or by binding to the Angptl3/Angptl8 complex to cancel out its inhibition of LPL, causing an increase in LPL activity to lower plasma TG levels [ 83 ]. Cell cultures have found that SCFAs such as butyrate lead to higher Apo-A5 expression in vitro [ 102 ].…”

Section: Gut-microbiota-derived Metabolites In Dyslipidemia and Obesitymentioning

confidence: 99%

The Role of Gut Microbiota and Its Produced Metabolites in Obesity, Dyslipidemia, Adipocyte Dysfunction, and Its Interventions

2021

View full text Add to dashboard Cite

Obesity is becoming an increasing problem worldwide and is often, but not invariably, associated with dyslipidemia. The gut microbiota is increasingly linked to cardiovascular disease, nonalcoholic fatty liver disease, and type 2 diabetes mellitus. However, relatively little focus has been attributed to the role of gut-microbiota-derived metabolites in the development of dyslipidemia and alterations in lipid metabolism. In this review, we discuss current data involved in these processes and point out the therapeutic potentials. We cover the ability of gut microbiota metabolites to alter lipoprotein lipase action, VLDL secretion, and plasma triglyceride levels, and its effects on reverse cholesterol transport, adipocyte dysfunction, and adipose tissue inflammation. Finally, the current intervention strategies for treatment of obesity and dyslipidemia is addressed with emphasis on the role of gut microbiota metabolites and its ability to predict treatment efficacies.

show abstract

“…In vitro assays suggest that ApoA-V at concentration >3 µM inhibits LPL, which is supraphysiologic concentration and in vivo effect is therefore questionable [97]. A more plausible mode of action for ApoA-V in intravascular lipolysis has recently been formulated by Chen and coworkers, who took the low concentrations of plasma ApoA-V into account in their model [98]. They reported that ApoA-V interacts specifically and with very high affinity with ANGPTL3/ANGPTL8 complexes and in doing so it abrogates the LPL inhibitory effect of that complex [98].…”

Section: Apolipoprotein A-v As Positive Regulator Of Lpl Mediated Lipolysismentioning

confidence: 99%

The Importance of Lipoprotein Lipase Regulation in Atherosclerosis

et al. 2021

View full text Add to dashboard Cite

Lipoprotein lipase (LPL) plays a major role in the lipid homeostasis mainly by mediating the intravascular lipolysis of triglyceride rich lipoproteins. Impaired LPL activity leads to the accumulation of chylomicrons and very low-density lipoproteins (VLDL) in plasma, resulting in hypertriglyceridemia. While low-density lipoprotein cholesterol (LDL-C) is recognized as a primary risk factor for atherosclerosis, hypertriglyceridemia has been shown to be an independent risk factor for cardiovascular disease (CVD) and a residual risk factor in atherosclerosis development. In this review, we focus on the lipolysis machinery and discuss the potential role of triglycerides, remnant particles, and lipolysis mediators in the onset and progression of atherosclerotic cardiovascular disease (ASCVD). This review details a number of important factors involved in the maturation and transportation of LPL to the capillaries, where the triglycerides are hydrolyzed, generating remnant lipoproteins. Moreover, LPL and other factors involved in intravascular lipolysis are also reported to impact the clearance of remnant lipoproteins from plasma and promote lipoprotein retention in capillaries. Apolipoproteins (Apo) and angiopoietin-like proteins (ANGPTLs) play a crucial role in regulating LPL activity and recent insights into LPL regulation may elucidate new pharmacological means to address the challenge of hypertriglyceridemia in atherosclerosis development.

show abstract

ApoA5 lowers triglyceride levels via suppression of ANGPTL3/8-mediated LPL inhibition

Cited by 55 publications

References 51 publications

GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity

GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity

The Role of Gut Microbiota and Its Produced Metabolites in Obesity, Dyslipidemia, Adipocyte Dysfunction, and Its Interventions

The Importance of Lipoprotein Lipase Regulation in Atherosclerosis

Contact Info

Product

Resources

About