Angptl3 regulates lipid metabolism in mice

Koishi, Ryuta; Ando, Yumiko; Ono, Mariko; Shimamura, Mitsuru; Yasumo, Hiroaki; Fujiwara, Toshihiko; Horikoshi, Hiroyoshi; Furukawa, Hidehiko

doi:10.1038/ng814

Cited by 375 publications

(346 citation statements)

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“…Inactivation of either gene in mice results in hypotriglyceridemia (5,32), and both genes elevate plasma TAG levels when expressed at high levels. Humans with complete ANGPTL3 deficiency have very low plasma levels of LDL-C, HDL-C, and TAG (4).…”

Section: Discussionmentioning

confidence: 99%

“…Genetic studies have revealed that two closely related family members, ANGPTL3 and ANGPTL4, play pivotal roles in the trafficking and metabolism of lipids and lipoproteins (4)(5)(6)(7). Mutations that disrupt ANGPTL3 are associated with greatly reduced plasma levels of triacylglycerol (TAG) and cholesterol in mice (5) and in humans (4). Mice lacking ANGPTL4 also have markedly reduced levels of plasma TAG and cholesterol (8,9), and sequence variations in ANGPTL4 are associated with lower plasma TAG levels in humans (7).…”

mentioning

confidence: 99%

“…ANGPTL3 is expressed almost exclusively in the liver (5,6), and is only modestly regulated by food intake (12). Angptl3 −/− mice have increased LPL activity (8,13,14), and recombinant ANGPTL3 inhibits LPL in vitro (6,13,15,16), leading several investigators to propose that ANGPTL3 raises plasma TAG levels by inhibiting LPL activity (13,14).…”

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confidence: 99%

“…The family members share a common architecture, comprising an extended N-terminal domain and a C-terminal fibrinogen-like domain. Genetic studies have revealed that two closely related family members, ANGPTL3 and ANGPTL4, play pivotal roles in the trafficking and metabolism of lipids and lipoproteins (4)(5)(6)(7). Mutations that disrupt ANGPTL3 are associated with greatly reduced plasma levels of triacylglycerol (TAG) and cholesterol in mice (5) and in humans (4).…”

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confidence: 99%

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Atypical angiopoietin-like protein that regulates ANGPTL3

Quagliarini

Wang

Kozlitina

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

412

666

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Angiopoietin-like proteins (ANGPTLs) play major roles in the trafficking and metabolism of lipids. Inactivation of ANGPTL3, a gene located in an intron of DOCK7, results in very low levels of LDL-cholesterol (C), HDL-C and triglyceride (TAG). We identified another ANGPTL family member, ANGPTL8, which is located in the corresponding intron of DOCK6. A variant in this family member (rs2278426, R59W) was associated with lower plasma LDL-C and HDL-C levels in three populations. ANGPTL8 is expressed in liver and adipose tissue, and circulates in plasma of humans. Expression of ANGPTL8 was reduced by fasting and increased by refeeding in both mice and humans. To examine the functional relationship between the two ANGPTL family members, we expressed ANGPTL3 at physiological levels alone or together with ANGPTL8 in livers of mice. Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3. ANGPTL8 coimmunoprecipitated with the N-terminal domain of ANGPTL3 in plasma of these mice. In cultured hepatocytes, ANGPTL8 expression increased the appearance of N-terminal ANGPTL3 in the medium, suggesting ANGPTL8 may activate ANGPTL3. Consistent with this scenario, expression of ANGPTL8 in Angptl3 −/− mice failed to promote hypertriglyceridemia. Thus, ANGPTL8, a paralog of ANGPTL3 that arose through duplication of an ancestral DOCK gene, regulates postprandial TAG and fatty acid metabolism by controlling activation of its progenitor, and perhaps other ANGPTLs. Inhibition of ANGPTL8 provides a new therapeutic strategy for reducing plasma lipoprotein levels.T he angiopoietin-like (ANGPTL) genes encode a family of secreted proteins with pleiotropic effects on vascular cells (1), lipid metabolism (2), and stem cell biology (3). The family members share a common architecture, comprising an extended N-terminal domain and a C-terminal fibrinogen-like domain. Genetic studies have revealed that two closely related family members, ANGPTL3 and ANGPTL4, play pivotal roles in the trafficking and metabolism of lipids and lipoproteins (4-7). Mutations that disrupt ANGPTL3 are associated with greatly reduced plasma levels of triacylglycerol (TAG) and cholesterol in mice (5) and in humans (4). Mice lacking ANGPTL4 also have markedly reduced levels of plasma TAG and cholesterol (8, 9), and sequence variations in ANGPTL4 are associated with lower plasma TAG levels in humans (7).TAG synthesized in the gut and liver are incorporated into chylomicrons and very low density lipoproteins (VLDL), respectively, and delivered to peripheral tissues where they interact with lipoprotein lipase (LPL). LPL hydrolyzes the TAGs, releasing fatty acids to the adjacent tissues. Other intravascular lipases, including hepatic lipase and endothelial lipase, further remodel lipoprotein particles. Several lines of evidence suggest that ANGPTL3 and ANGPTL4 contribute to the partitioning of TAGs among tissues (2). During fasting, ANGPTL4 levels increase in ad...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Atypical angiopoietin-like protein that regulates ANGPTL3

Quagliarini

Wang

Kozlitina

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

412

666

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“…The ANGPTL3 protein is synthesized by the liver and secreted into the bloodstream 11 . It inhibits lipoprotein lipase 12 , thus delaying clearance of TRLs from the blood and increasing TRL blood concentrations ( Fig.…”

Section: S E K a R K At H I R E S A Nmentioning

confidence: 99%

Putative medicines that mimic mutations

Kathiresan

2017

Nature

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The Regulation of Triacylglycerol Metabolism and Lipoprotein Lipase Activity

2022

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Triacylglycerol (TG) metabolism is tightly regulated to maintain a pool of TG within circulating lipoproteins that can be hydrolyzed in a tissue‐specific manner by lipoprotein lipase (LPL) to enable the delivery of fatty acids to adipose or oxidative tissues as needed. Elevated serum TG concentrations, which result from a deficiency of LPL activity or, more commonly, an imbalance in the regulation of tissue‐specific LPL activities, have been associated with an increased risk of atherosclerotic cardiovascular disease through multiple studies. Among the most critical LPL regulators are the angiopoietin‐like (ANGPTL) proteins ANGPTL3, ANGPTL4, and ANGPTL8, and a number of different apolipoproteins including apolipoprotein A5 (ApoA5), apolipoprotein C2 (ApoC2), and apolipoprotein C3 (ApoC3). These ANGPTLs and apolipoproteins work together to orchestrate LPL activity and therefore play pivotal roles in TG partitioning, hydrolysis, and utilization. This review summarizes the mechanisms of action, epidemiological findings, and genetic data most relevant to these ANGPTLs and apolipoproteins. The interplay between these important regulators of TG metabolism in both fasted and fed states is highlighted with a holistic view toward understanding key concepts and interactions. Strategies for developing safe and effective therapeutics to reduce circulating TG by selectively targeting these ANGPTLs and apolipoproteins are also discussed.

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Angptl3 regulates lipid metabolism in mice

Cited by 375 publications

References 35 publications

Atypical angiopoietin-like protein that regulates ANGPTL3

Atypical angiopoietin-like protein that regulates ANGPTL3

Putative medicines that mimic mutations

The Regulation of Triacylglycerol Metabolism and Lipoprotein Lipase Activity

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