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Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion.

ABSTRACT: Humans and mice lacking angiopoietin-like protein 3 (ANGPTL3) have pan-hypolipidemia. ANGPTL3 inhibits two intravascular lipases, LPL and endothelial lipase, and the low plasma TG and HDL-cholesterol levels in ANGPTL3 deficiency reflect increased activity of these enzymes. The mechanism responsible for the low LDL-cholesterol levels associated with ANGPTL3 deficiency is not known. Here we used an anti-ANGPTL3 monoclonal antibody (REGN1500) to inactivate ANGPTL3 in mice with genetic deficiencies in key proteins involved in clearance of ApoB-containing lipoproteins. REGN1500 treatment consistently reduced plasma cholesterol levels in mice in which Apoe, Ldlr, Lrp1, and Sdc1 were inactivated singly or in combination, but did not alter clearance of rabbit (125)I-?VLDL or mouse (125)I-LDL. Despite a 61% reduction in VLDL-TG production, VLDL-ApoB-100 production was unchanged in REGN1500-treated animals. Hepatic TG content, fatty acid synthesis, and fatty acid oxidation were similar in REGN1500 and control antibody-treated animals. Taken together, our findings indicate that inactivation of ANGPTL3 does not affect the number of ApoB-containing lipoproteins secreted by the liver but alters the particles that are made such that they are cleared more rapidly from the circulation via a noncanonical pathway(s). The increased clearance of lipolytic remnants results in decreased production of LDL in ANGPTL3-deficient animals.

SUBMITTER: Wang Y

PROVIDER: S-EPMC4479334 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion.

Wang Yan Y Gusarova Viktoria V Banfi Serena S Gromada Jesper J Cohen Jonathan C JC Hobbs Helen H HH

Journal of lipid research 20150507 7

Humans and mice lacking angiopoietin-like protein 3 (ANGPTL3) have pan-hypolipidemia. ANGPTL3 inhibits two intravascular lipases, LPL and endothelial lipase, and the low plasma TG and HDL-cholesterol levels in ANGPTL3 deficiency reflect increased activity of these enzymes. The mechanism responsible for the low LDL-cholesterol levels associated with ANGPTL3 deficiency is not known. Here we used an anti-ANGPTL3 monoclonal antibody (REGN1500) to inactivate ANGPTL3 in mice with genetic deficiencies ...[more]

PMID: 25954050

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Project description:ContextThe exact mechanisms responsible for increased plasma triglyceride (TG) concentration in obese people are unclear, and it is not known whether excess energy intake per se is involved in the pathophysiology of this abnormality.ObjectiveThe purpose of our study was to examine how excess energy intake from a balanced diet for 1 day affects very-low-density lipoprotein (VLDL)-TG kinetics and its putative regulators hepatic insulin sensitivity and plasma free fatty acid availability.Subjects and designWe used stable isotope-labeled tracer methods to evaluate glucose and lipid kinetics in 8 overweight and obese men (age, 38 ± 3 years; body mass index, 33.7 ± 1.7 kg/m(2); means ± SEM) on 2 occasions (randomized crossover design): once, the day after they consumed a balanced diet that provided an amount of energy that matched their energy expenditure, and another time, the day after they consumed a balanced diet that provided 30% excess calories. Eight healthy, lean men (34 ± 1 years; 22.5 ± 0.6 kg/m(2)) were studied under isocaloric conditions only to provide a reference for normal lipid kinetics.ResultsVLDL-TG and VLDL-apolipoprotein B-100 (apoB-100) concentrations and secretion rates were significantly greater (P < .01) in overweight/obese compared with lean men. Hypercaloric, compared with isocaloric, feeding in overweight/obese men increased glucose rate of appearance in plasma (904 ± 21 vs 873 ± 26 μmol/min), the hepatic insulin resistance index (10.9 ± 2.2 vs 8.3 ± 1.8), and VLDL-apoB-100 concentration and secretion rate (1.91 ± 0.24 vs. 1.53 ± 0.13 nmol/min), whereas VLDL-apoB-100 plasma clearance rate, VLDL-TG secretion and plasma clearance rates, and free fatty acid rate of appearance in plasma were not affected by overfeeding.ConclusionOne day of moderate overfeeding (30% excess energy intake) stimulates hepatic glucose and VLDL-apo B-100 secretion rates but has no effect on hepatic and adipose tissue fatty acid metabolism in overweight/obese men.

Project description:Background and Aims: Inflammasome-mediated caspase-1 activity regulates the maturation and release of the pro-inflammatory cytokines interleukin (IL)-1M-CM-^_ and IL-18. Recently, we showed that caspase-1 deficiency strongly reduces high fat diet-induced adiposity although the mechanism is still unclear. We now aimed to elucidate the mechanism by which caspase-1 deficiency reduces modulates resistance to high fat diet-feeding fat accumulation in adipose tissue by focusing on the role of caspase-1 in the regulation of triglyceride (TG)-rich lipoprotein metabolism. Methods: Caspase-1 deficient and wild-type mice (both C57Bl/6 background) were used to determine postprandial TG kinetics, intestinal TG absorption, VLDL-TG production as well as TG clearance, all of which strongly contribute to the supply of TG for storage in adipose tissue. Micro-array and qPCR analysis were used to unravel intestinal and hepatic metabolic pathways involved. Results: Caspase-1 deficiency reduced the postprandial response to an oral lipid load, while tissue specific clearance of TG-rich lipoproteins was not changed. Indeed, an oral olive oil gavage containing [3H]TG revealed that caspase-1 deficiency significantly decreased intestinal chylomicron-TG production and reduced the uptake of [3H]TG-derived FA by liver, muscle, and adipose tissue. Similarly, caspase-1 deficiency reduced the hepatic VLDL-TG production without reducing VLDL-apoB production, despite an elevated hepatic TG content. Pathway analysis revealed that caspase-1 deficiency reduces intestinal and hepatic expression of genes involved in lipogenesis. Conclusions: Absence of caspase-1 reduces assembly and secretion of TG-rich lipoproteins, thereby reducing the availability of TG-derived FA for uptake by peripheral organs including adipose tissue. We anticipate that caspase-1 represents a novel link between innate immunity and lipid metabolism. Keywords: Expression profiling by array Wild-type (WT) and Casp1-null mice were maintained at lab chow. Animals, aged between 14 and 16 weeks (n=3 per genotype), were killed and liver and intestinal segments were removed. Livers were isolated from mice that were fasted over night, whereas intesines were removed from mice 2 hrs after they received an oral lipid load.Total RNA was isolated and subjected to gene expression profiling.

Dataset Information

Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion.

Publications

Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion.

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