FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice

Kamagaté, Adama; Qu, Shen; Perdomo, Germán; Su, Dongming; Kim, Dae Hyun; Slusher, Sandra; Meseck, Marcia; Dong, H. Henry

doi:10.1172/jci32914

Cited by 188 publications

(260 citation statements)

References 85 publications

(120 reference statements)

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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%

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%

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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“…In this tissue, FoxO1 increases VLDL production (hence, delivery of triglycerides to skeletal muscle for oxidation) by up-regulating the expression of microsomal triglyceride transfer protein (35). Thus, FoxO1 increases lipolysis in fat tissue, stimulates VLDL production in the liver, and boosts lipid oxidation in skeletal muscle; in other words, FoxO1 may be considered as an important regulator of lipid homeostasis and partitioning of triglycerides between different tissues of the mammalian organism.…”

Section: Discussionmentioning

confidence: 99%

FoxO1 Controls Insulin-dependent Adipose Triglyceride Lipase (ATGL) Expression and Lipolysis in Adipocytes

Chakrabarti

Kandror

2009

Journal of Biological Chemistry

192

169

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FoxO1 represents a central regulator of metabolism in several cell types. Although FoxO1 is abundant in adipocytes, its biological functions in these cells remain largely unknown. We show here that the promotor region of the rate-limiting lipolytic enzyme, adipose triglyceride lipase (ATGL), has two FoxO1-binding sites, and co-transfection with wild type and unphosphorylated FoxO1 mutant activates the expression of luciferase driven by the ATGL promotor. In 3T3-L1 adipocytes, insulin controls nucleo-cytoplasmic shuttling of FoxO1 and regulates its interaction with endogenous ATGL promotors. Knockdown of FoxO1 in 3T3-L1 adipocytes decreases the expression of ATGL and attenuates basal and isoproterenol-stimulated lipolysis. Infection of mouse embryonic fibroblasts with FoxO1-encoding lentivirus increases ATGL expression and renders it sensitive to regulation by insulin. Thus, FoxO1 may play an important role in the regulation of lipolysis in adipocytes by controlling the expression of ATGL.One of the key physiological functions of insulin in the mammalian organism is to inhibit lipolysis and to promote accumulation and storage of triglycerides in fat tissue. Control of lipolysis plays an important role in energy partitioning and balance and maintains the size of fat depots in the body. In patients with insulin resistance and type 2 diabetes, insulin cannot suppress high levels of free fatty acids (FFA) 2 in the bloodstream (1) so that the availability of FFA exceeds the energy requirements of the body. As a result, FFA are accumulated in the form of lipids in non-adipose peripheral tissues, such as liver and skeletal muscle, aggravating insulin resistance and causing multiple hazardous metabolic effects (2, 3). In addition, excess of FFA may lead to overproduction of VLDL in the liver and predispose the organism to cardiovascular disease.The complete hydrolysis of triglycerides to glycerol and FFA is performed jointly by tri-, di-, and monoacylglyceride lipases (4, 5). Recently discovered adipose triglyceride lipase ATGL (6 -8) is responsible for the bulk of triacylglycerol hydrolase activity in cells and has low affinity to di-and monoacylglycerides (4, 5). Importantly, ATGL is now considered the rate-limiting lipolytic enzyme in mammals (9), flies (10), and yeast (11). The major diacylglyceride lipase in adipocytes is hormone-sensitive lipase, or HSL (5). ATGL-and HSL-mediated hydrolase activity is controlled by catecholamines primarily via the cAMP-mediated-phosphorylation of perilipin (12, 13), the major lipid droplet-forming protein in adipocytes (14). Monoacylglyceride lipase in adipocytes is believed to be hormone-independent (4).The effect of insulin on lipolysis is attributed to the stimulation of activity and/or the expression of cyclic nucleotide phosphodiesterases 3B and 4 (15-17), which decrease intracellular levels of cAMP and reverse the stimulatory effect of cAMP-dependent protein kinase on lipolysis (5). In parallel, insulin may suppress lipolysis in a cAMP-independent fashion by stimulating pro...

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“…The extraction of nuclear and cytosolic fractions from fetal islet was performed using a Pierce Nucleus/Cytosolic kit (Fisher, Nepean, ON, Canada) according to the manufacturer's instructions [24]. Equal amounts (35 μg) of extracted proteins from each experimental group were separated by 10% SDS-PAGE (vol./ vol.)…”

Section: Protein Extraction and Western Blot Analysismentioning

confidence: 99%

Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

et al. 2009

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Aims/hypothesis Recent studies have demonstrated that in adult murine beta cells the forkhead box O1 (FOXO1) transcription factor regulates proliferation and stress resistance. However, the role of FOXO1 during pancreatic development remains largely unknown. The present study aimed to characterise the expression of the FOXO1 transcription factor in the early to mid-gestation human fetal pancreas and to understand its role in islet cell development. Methods Human (8-21 week fetal age) pancreases were examined using immunohistological, quantitative RT-PCR and western blotting. Isolated human (18-21 week) fetal islet epithelial cell clusters were treated with insulin or glucose, or transfected with FOXO1 small interfering RNA (siRNA). Results Nuclear and cytoplasmic FOXO1 were widely produced during human fetal endocrine pancreatic development, co-localising in cells with the transcription factors pancreatic and duodenal homeobox 1 (PDX-1) and neurogenin 3 (NGN3) as well as cytokeratin 19 (CK19), insulin and glucagon. Treatment with exogenous insulin (50 nmol/l) induced the nuclear exclusion of FOXO1 in both cytokeratin 19 (CK19) + (p<0.01) and insulin + cells (p<0.05) in parallel with increased phospho-Akt (p<0.05) production. siRNA knockdown of FOXO1 significantly increased the number of NGN3 + (p<0.01) and NK6 homeobox 1 (NKX6-1) + (p<0.05) cells in parallel with increases in insulin gene expression (p<0.03) and C-peptide + cells (p<0.05) and reduced levels of hairy and enhancer of split 1 (HES1) (p<0.01). Conclusions/interpretation Our results indicate that FOXO1 may negatively regulate beta cell differentiation in the human fetal pancreas by controlling critical transcription factors, including NGN3 and NKX6-1. These data suggest that the manipulation of FOXO1 levels may be a useful tool for improving cell-based strategies for the treatment of diabetes.Keywords Human fetal pancreas . Human islet epithelial cell clusters . Islet transcription factors . Nuclear FOXO1 . FOXO1 siRNA Electronic supplementary material The online version of this article

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FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice

Cited by 188 publications

References 85 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

FoxO1 Controls Insulin-dependent Adipose Triglyceride Lipase (ATGL) Expression and Lipolysis in Adipocytes

Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

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