Apolipoprotein C-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL

Larsson, Mikael; Allan, Christopher M.; Jung, Rachel S.; Heizer, Patrick J.; Beigneux, Anne P.; Young, Stephen G.; Fong, Loren G.

doi:10.1194/jlr.m078220

Cited by 44 publications

(38 citation statements)

References 36 publications

(35 reference statements)

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“…Subsequently, we compared the serum levels of TG and VLDL in HBV patients and normal controls and found that the serum levels of TG and VLDL were lower in HBV patients. ApoC3 is a lipoprotein lipase (LPL) inhibitor, which can inhibit the activities of lipase, hepatic lipase and lecithin cholesterol acyltransferase to affect lipid metabolism [ 27 , 28 ]. LPL is a key enzyme in the catabolism of triglyceride lipoprotein (TRL) [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus inhibits the in vivo and in vitro synthesis and secretion of apolipoprotein C3

Zhu

Song

et al. 2017

Lipids Health Dis

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BackgroundHepatitis B virus (HBV) infection in the body can damage liver cells and cause disorders in blood lipid metabolism. Apolipoprotein C3 (ApoC3) plays an important role in the regulation of lipid metabolism, but no study on the HBV regulation of ApoC3 has been reported. This purpose of this study was to investigate the effect of HBV on ApoC3 expression and its regulatory mechanism.MethodsThe expression levels of ApoC3 mRNA and protein in the human hepatoma cell lines HepG2 and HepG2.2.15 were determined using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot. The HepG2 cells were co-transfected with the ApoC3 gene promoter and either HBV-infected clone pHBV1.3 or its individual genes. The changes in luciferase activity were assayed. The expression levels of ApoC3 mRNA and protein were determined using RT-qPCR and Western blot. The content of ApoC3 in the supernatant of the cultured cells was determined using an enzyme-linked immunosorbent assay (ELISA). The sera were collected from 149 patients with HBV infection and 102 healthy subjects at physical examination as the normal controls. The serological levels of ApoC3 in the HBV group and the normal control group were determined using ELISA. The contents of serum triglyceride (TG) and very-low-density lipoprotein (VLDL) in the HBV patients and the normal control were determined using an automatic biochemical analyser.ResultsThe expression levels of ApoC3 mRNA and protein were lower in the HepG2.2.15 cells than in the HepG2 cells. pHBV1.3 and its X gene could inhibit the activity of the ApoC3 promoter and its mRNA and protein expression. The serum levels of ApoC3, VLDL and TG were 65.39 ± 7.48 μg/ml, 1.24 ± 0.49 mmol/L, and 0.46 ± 0.10 mmol/L in the HBV patients and 41.02 ± 6.88 μg/ml, 0.76 ± 0.21 mmol/L, 0.29 ± 0.05 mmol/L in the normal controls, respectively, statistical analysis revealed significantly lower serum levels of ApoC3, VLDL and TG in HBV patients than in the normal controls (P < 0.05).ConclusionHBV can inhibit the in vivo and in vitro synthesis and secretion of ApoC3.

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Section: Discussionmentioning

confidence: 99%

Hepatitis B virus inhibits the in vivo and in vitro synthesis and secretion of apolipoprotein C3

Zhu

Song

et al. 2017

Lipids Health Dis

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“…suggesting that the higher LPL activity in BAT during cold exposure (35,36) outweighs the ability of apoC-III to limit LPL accessibility to triglyceride substrates (33,34). We also examined mice deficient in both apoC-III and GPIHBP1 (Gpihbp1 −/− Apoc3 −/− ).…”

Section: Resultsmentioning

confidence: 99%

Impaired thermogenesis and sharp increases in plasma triglyceride levels in GPIHBP1-deficient mice during cold exposure

Larsson

Allan

Heizer

et al. 2018

Journal of Lipid Research

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Glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1), an endothelial cell protein, binds LPL in the subendothelial spaces and transports it to the capillary lumen. In Gpihbp1−/− mice, LPL remains stranded in the subendothelial spaces, causing hypertriglyceridemia, but how Gpihbp1−/− mice respond to metabolic stress (e.g., cold exposure) has never been studied. In wild-type mice, cold exposure increases LPL-mediated processing of triglyceride-rich lipoproteins (TRLs) in brown adipose tissue (BAT), providing fuel for thermogenesis and leading to lower plasma triglyceride levels. We suspected that defective TRL processing in Gpihbp1−/− mice might impair thermogenesis and blunt the fall in plasma triglyceride levels. Indeed, Gpihbp1−/− mice exhibited cold intolerance, but the effects on plasma triglyceride levels were paradoxical. Rather than falling, the plasma triglyceride levels increased sharply (from ∼4,000 to ∼15,000 mg/dl), likely because fatty acid release by peripheral tissues drives hepatic production of TRLs that cannot be processed. We predicted that the sharp increase in plasma triglyceride levels would not occur in Gpihbp1−/−Angptl4−/− mice, where LPL activity is higher and baseline plasma triglyceride levels are lower. Indeed, the plasma triglyceride levels in Gpihbp1−/−Angptl4−/− mice fell during cold exposure. Metabolic studies revealed increased levels of TRL processing in the BAT of Gpihbp1−/−Angptl4−/− mice.

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“…Studies in humans have convincingly demonstrated that APOC3 loss-of-function mutations lower TRL levels and offer cardioprotection (15)(16)(17)(18)(19)(20). APOC3 was long believed to elevate plasma TRL levels by inhibiting lipoprotein lipase (14,21), but a human antisense oligonucleotide (ASO) therapeutic against APOC3 markedly reduced triglyceride (TG) levels in lipoprotein lipase-deficient humans with severe hypertriglyceridemia (22). quantified by targeted mass spectrometry (MS).…”

Section: Introductionmentioning

confidence: 99%

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes

Kanter¹,

Shao²,

Kramer³

et al. 2019

Journal of Clinical Investigation

142

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Type 1 diabetes mellitus (T1DM) increases the risk of atherosclerotic cardiovascular disease (CVD) in humans by poorly understood mechanisms. Using mouse models of T1DM-accelerated atherosclerosis, we found that relative insulin deficiency, rather than hyperglycemia, elevated levels of apolipoprotein C3 (APOC3), an apolipoprotein that prevents clearance of triglyceride-rich lipoproteins (TRLs) and their remnants. We then showed that serum APOC3 levels predict incident CVD events in subjects with T1DM in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. To explore underlying mechanisms, we examined the impact of Apoc3 antisense oligonucleotides (ASOs) on lipoprotein metabolism and atherosclerosis in a mouse model of T1DM. Apoc3 ASO treatment abolished the increased hepatic expression of Apoc3 in diabetic mice, resulting in lower levels of TRLs, without improving glycemic control. APOC3 suppression also prevented arterial accumulation of APOC3-containing lipoprotein particles, macrophage foam cell formation, and accelerated atherosclerosis in diabetic mice. Our observations demonstrate that relative insulin deficiency increases APOC3 and that this results in elevated levels of TRLs and accelerated atherosclerosis in a mouse model of T1DM. Because serum levels of APOC3 predicted incident CVD events in the CACTI study, inhibition of APOC3 might reduce CVD risk in patients with T1DM.

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Apolipoprotein C-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL

Cited by 44 publications

References 36 publications

Hepatitis B virus inhibits the in vivo and in vitro synthesis and secretion of apolipoprotein C3

Hepatitis B virus inhibits the in vivo and in vitro synthesis and secretion of apolipoprotein C3

Impaired thermogenesis and sharp increases in plasma triglyceride levels in GPIHBP1-deficient mice during cold exposure

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes

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