PI3-kinase activity modulates apo B available for hepatic VLDL production inapobec-1−/−mice

Chirieac, Doru V.; Davidson, Nicholas O.; Sparks, Charles E.; Sparks, Janet D.

doi:10.1152/ajpgi.00472.2005

Cited by 41 publications

(38 citation statements)

References 37 publications

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“…The interface between PI3K-dependent signaling and apoB assembly and secretion is not known in detail, although in some studies, insulin-mediated signaling, via PI3K and Akt, regulates MTP expression and, hence, VLDL particle number and size (18,29,31,32). Although MTP is the target for some forms of PI3K-mediated regulation of VLDL assembly (32), MTP expression was unaffected by ABCA1 deficiency in this study (Fig.…”

Section: Discussionmentioning

confidence: 66%

“…To study the effect of in vivo inhibition of PI3K on VLDL TG and apoB production, mice were injected with the PI3K inhibitor wortmannin (1.5 g/g body weight) 1 h prior to detergent injection as described previously (18). Fifty l of blood were collected from anesthetized mice by retro-orbital bleeding at 0, 1, 2, and 4 h after injection.…”

Section: Animals and Diet-generationmentioning

confidence: 99%

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Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

Chung

Timmins

Duong

et al. 2010

Journal of Biological Chemistry

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Loss of ABCA1 activity in Tangier disease (TD) is associated with abnormal apoB lipoprotein (Lp) metabolism in addition to the complete absence of high density lipoprotein (HDL). We used hepatocyte-specific ABCA1 knock-out (HSKO) mice to test the hypothesis that hepatic ABCA1 plays dual roles in regulating Lp metabolism and nascent HDL formation. HSKO mice recapitulated the TD lipid phenotype with postprandial hypertriglyceridemia, markedly decreased LDL, and near absence of HDL. Triglyceride (TG) secretion was 2-fold higher in HSKO compared with wild type mice, primarily due to secretion of larger TG-enriched VLDL secondary to reduced hepatic phosphatidylinositol 3-kinase signaling. HSKO mice also displayed delayed clearance of postprandial TG and reduced post-heparin plasma lipolytic activity. In addition, hepatic LDLr expression and plasma LDL catabolism were increased 2-fold in HSKO compared with wild type mice. Last, adenoviral repletion of hepatic ABCA1 in HSKO mice normalized plasma VLDL TG and hepatic phosphatidylinositol 3-kinase signaling, with a partial recovery of HDL cholesterol levels, providing evidence that hepatic ABCA1 is involved in the reciprocal regulation of apoB Lp production and HDL formation. These findings suggest that altered apoB Lp metabolism in TD subjects may result from hepatic VLDL TG overproduction and increased hepatic LDLr expression and highlight hepatic ABCA1 as an important regulatory factor for apoB-containing Lp metabolism. ABCA1 (ATP-binding cassette transporter A1) is indispensable in the initial steps of high density lipoprotein (HDL)2 formation and the process of reverse cholesterol transport from peripheral tissues to the liver. ABCA1 is expressed in many cells; however, hepatocytes make the single most important contribution to plasma HDL concentration (1-3). Mutations in ABCA1 in humans cause Tangier disease (TD), an autosomal recessive disorder characterized by severe HDL deficiency, rapid plasma clearance of HDL and apoA-I, sterol deposition in tissues, and premature coronary atherosclerosis (4 -7). In addition to HDL deficiency, TD subjects have significantly elevated plasma TG and a 50% reduction in LDL cholesterol concentrations (4,8). The TG phenotype in TD disease is complicated, with most, but not all, TD subjects displaying elevated fasting or postprandial TG elevations (9). Clee et al. (8) reported an inverse relationship between dysfunctional ABCA1 alleles and plasma TG concentrations. In addition, data from case reports of 59 Tangier patients show variable TG concentrations, with mean, median, minimum, and maximum concentrations of 210, 175, 40, and 580 mg/dl, respectively (4). The underlying mechanisms for the increased plasma TG and decreased LDL concentrations in TD subjects have not been established. In one study, apoA-II enrichment of VLDL of TD subjects was proposed to result in reduced reactivity of VLDL with lipoprotein lipase (LPL) (9, 10). Another study suggested that ABCA1-dependent cholesterol efflux decreases VLDL secretion from murine hep...

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Section: Discussionmentioning

confidence: 66%

Section: Animals and Diet-generationmentioning

confidence: 99%

Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

Chung

Timmins

Duong

et al. 2010

Journal of Biological Chemistry

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“…kinase pathways ( 30,31,46,47 ). Insulin stimulation appears to specifi cally inhibit the second step of VLDL assembly such that insulin resistance results in increased hepatic production of VLDL1 ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

A novel role for ABCA1-generated large pre- migrating nascent HDL in the regulation of hepatic VLDL triglyceride secretion

Chung

Gebre

Seo

et al. 2010

The Journal of Lipid Research

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ABCA1 is a membrane protein that transports phospholipid (PL) and free cholesterol (FC) across cell membranes, to combine with lipid-free apolipoprotein (apo) A-I , forming nascent HDL particles ( 1 ). Mutations in ABCA1 that inactivate its function cause Tangier disease, which is characterized by a severe HDL defi ciency, rapid clearance of apoA-I from plasma, deposition of sterol in macrophage-rich tissues, and premature coronary heart disease ( 2-5 ). ABCA1 is expressed in many cells, but hepatocytes are the single most important cell type in determining plasma HDL concentrations, contributing 70-80% of the HDL pool in mice ( 6, 7 ). Recently, we have shown that ABCA1 expression is necessary and suffi cient for formation of heterogeneous-sized pre-␤ migrating nascent HDL subspecies (pre-␤ 1, 2, 3, and 4 HDL), which vary in size from 7.1 to 15.7 nm ( 8 ). Although electrophoretic mobility (pre-␤ vs. ␣ migration) of discoidal nascent HDLs is dependent on cell type and culture conditions, similar distinct-sized subspecies of nascent HDL are formed by most cell types tested, including fi broblasts ( 9, 10 ), macrophages, hepatocytes, and ABCA1-expressing human embryonic kidney (HEK)293 cells ( 11 ). The importance of nascent HDL size heterogeneity in the physiology and pathophysiology of HDL metabolism is poorly understood.ABCA1 expression also affects plasma VLDL and LDL concentrations. In addition to the near absence of plasma HDL, many homozygous Tangier disease patients have Abstract In Tangier disease, absence of ATP binding cassette transporter A1 (ABCA1) results in reduced plasma HDL and elevated triglyceride (TG) levels. We hypothesized that hepatocyte ABCA1 regulates VLDL TG secretion through nascent HDL production. Silencing of ABCA1 expression in oleate-stimulated rat hepatoma cells resulted in: 1 ) decreased large nascent HDL (>10 nm diameter) and increased small nascent HDL (<10 nm) formation, 2 ) increased large buoyant VLDL1 particle secretion, and 3 ) decreased phosphatidylinositol-3 (PI3) kinase activation. Nascent HDL-containing conditioned medium from rat hepatoma cells or HEK293 cells transfected with ABCA1 was effective in increasing PI3 kinase activation and reducing VLDL TG secretion in ABCA1-silenced hepatoma cells. Addition of isolated large nascent HDL particles to ABCA1-silenced hepatoma cells inhibited VLDL TG secretion to a greater extent than small nascent HDL. Similarly, addition of recombinant HDL, but not human plasma HDL, was effective in attenuating TG secretion and increasing PI3 kinase activation in ABCA1-silenced cells. Collectively, these data suggest that large nascent HDL particles, assembled by hepatic ABCA1, generate a PI3 kinase-mediated autocrine signal that attenuates VLDL maturation and TG secretion. This pathway may explain the elevated plasma TG concentration that occurs in most Tangier subjects and may also account, in part, for the inverse relationship between plasma HDL and TG concentrations in individuals with compromised ABCA1 function. -Chung, S., A. K. Gebre...

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“…In rat hepatocytes, insulin was shown to inhibit the maturation phase of VLDL assembly by preventing lipid transfer to pre-VLDL particles, resulting in preferential degradation of apoB-100 from these pre-VLDL particles (26). Furthermore, Chirieac et al (27) examined apoB-100 secretion by pulse-chase in primary mouse hepatocytes and concluded that blocking the effect of insulin with wortmannin increased the amount of apoB-100 available for secretion. It was not possible to distinguish decreased synthesis from increased cotranslational degradation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of apoB secretion from HepG2 cells by insulin is amplified by naringenin, independent of the insulin receptor

Allister

Mulvihill

Barrett

et al. 2008

Journal of Lipid Research

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Hepatic overproduction of apolipoprotein B (apoB)-containing lipoproteins is characteristic of the dyslipidemia associated with insulin resistance. Recently, we demonstrated that the flavonoid naringenin, like insulin, decreased apoB secretion from HepG2 cells by activation of both the phosphoinositide-3-kinase (PI3-K) pathway and the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK erk ) pathway. In the present study, we determined whether naringenin-induced signaling required the insulin receptor (IR) and sensitized the cell to the effects of insulin, and whether the kinetics of apoB assembly and secretion in cells exposed to naringenin were similar to those of insulin. Immunoblot analysis revealed that insulin stimulated maximal phosphorylation of IR and IR substrate-1 after 10 min, whereas naringenin did not affect either at any time point up to 60 min. The combination of naringenin and submaximal concentrations of insulin potentiated extracellularregulated kinase 1/2 activation and enhanced upregulation of the LDL receptor, downregulation of microsomal triglyceride transfer protein expression, and inhibition of apoB-100 secretion. Multicompartmental modeling of apoB pulse-chase studies revealed that attenuation of secreted radiolabeled apoB in naringenin-or insulin-treated cells was similar under lipoprotein-deficient or oleate-stimulated conditions. Naringenin and insulin both stimulated intracellular apoB degradation via a kinetically defined rapid pathway. Therefore, naringenin, like insulin, inhibits apoB secretion through activation of both PI3-K and MAPK erk signaling, resulting in similar kinetics of apoB secretion. However, the mechanism for naringenin-induced signaling is independent of the IR. Naringenin represents a possible strategy for reduction of hepatic apoB secretion, particularly in the setting of insulin

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PI3-kinase activity modulates apo B available for hepatic VLDL production inapobec-1^−/−mice

Cited by 41 publications

References 37 publications

Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

A novel role for ABCA1-generated large pre- migrating nascent HDL in the regulation of hepatic VLDL triglyceride secretion

Inhibition of apoB secretion from HepG2 cells by insulin is amplified by naringenin, independent of the insulin receptor

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