Direct effects of growth hormone on production and secretion of apolipoprotein B from rat hepatocytes

Lindén, Daniel; Sjöberg, A; Asp, Lennart; Carlsson, Linda; Oscarsson, Jan

doi:10.1152/ajpendo.2000.279.6.e1335

Cited by 30 publications

(45 citation statements)

References 51 publications

(89 reference statements)

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“…We have previously observed that GH incubation of hepatocytes using the same culture conditions as used in this study results in a 50% increase in triglyceride synthesis (28). Taken together, our results indicate that increased expression of SREBP-1c, FAS, or GPAT mRNA is not necessary for an effect of GH on triglyceride biosynthesis in vitro.…”

supporting

confidence: 76%

Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver

Améen¹,

Lindén²,

Larsson³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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. Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver. Am J Physiol Endocrinol Metab 287: E1039 -E1048, 2004. First published July 27, 2004 doi:10.1152/ ajpendo.00059.2004.-We investigated whether the sexually dimorphic secretory pattern of growth hormone (GH) in the rat regulates hepatic gene expression of sterol regulatory element-binding protein-1c (SREBP-1c) and its target genes. SREBP-1c, fatty acid synthase (FAS), and glycerol-3-phosphate acyltransferase (GPAT) mRNA were more abundant in female than in male livers, whereas acetyl-CoA carboxylase-1 (ACC1) and stearoyl-CoA desaturase-1 (SCD-1) were similarly expressed in both sexes. Hypophysectomized female rats were given GH as a continuous infusion or as two daily injections for 7 days to mimic the female-and male-specific GH secretory patterns, respectively. The female pattern of GH administration increased the expression of SREBP-1c, ACC1, FAS, SCD-1, and GPAT mRNA, whereas the male pattern of GH administration increased only SCD-1 mRNA. FAS and SCD-1 protein levels were regulated in a similar manner by GH. Incubation of primary rat hepatocytes with GH increased SCD-1 mRNA levels and decreased FAS and GPAT mRNA levels but had no effect on SREBP-1c mRNA. GH decreased hepatic liver X receptor-␣ (LXR␣) mRNA levels both in vivo and in vitro. Feminization of the GH plasma pattern in male rats by administration of GH as a continuous infusion decreased insulin sensitivity and increased expression of FAS and GPAT mRNA but had no effect on SREBP-1c, ACC1, SCD-1, or LXR␣ mRNA. In conclusion, FAS and GPAT are specifically upregulated by the female secretory pattern of GH. This regulation is not a direct effect of GH on hepatocytes and does not involve changed expression of SREBP-1c or LXR␣ mRNA but is associated with decreased insulin sensitivity. growth hormone; hypophysectomy; acetyl-CoA carboxylase; fatty acid synthase; stearoyl-CoA desaturase; glycerol-3-phosphate acyltransferase; liver X receptor-␣; insulin sensitivity GROWTH HORMONE (GH) plays an important role in the regulation of lipid metabolism. GH has lipolytic and antilipogenic effects in adipose tissue (6) that contribute to the decreased body fat mass observed after GH treatment (2, 42). Elevation of plasma GH levels also results in increased plasma insulin levels and insulin resistance (6). The increased insulin secretion can be explained by a direct effect of GH on the pancreatic ␤-cells (33, 40), whereas the insulin resistance may be explained by increased fatty acid oxidation in some (34), but not all, situations (18, 37).GH secretion from the pituitary is sexually differentiated in all mammals, but the difference is particularly pronounced in rodents (8,17,21). In female rats, the GH secretion is frequent and nearly continuous with high basal levels, whereas GH is secreted as regular, high-amplitude pulses with low or undetectable levels between peaks in males (8, 46). Several hepatic functions that are sex differentiated a...

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supporting

confidence: 76%

Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver

Améen¹,

Lindén²,

Larsson³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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“…The secretion of apoB-48 and apoB-100 from primary mouse hepatocyte cultures was estimated by labeling the cells with a [ 35 S]methionine-cysteine mix (Amersham Biosciences) for 2 h followed by a 4 h chase in culture medium supplemented with 10 mM methionine, as described (38,43,44). Labeled apoB-48 and apoB-100 were isolated by immunoprecipitation with 10 Al of polyclonal rabbit anti-human apoB antibodies (DakoCytomation, Glostrup, Denmark), followed by 5% polyacrylamide gel electrophoresis containing SDS.…”

Section: Estimation Of Apob Secretionmentioning

confidence: 99%

PPARα activation increases triglyceride mass and adipose differentiation-related protein in hepatocytes

Edvardsson

Ljungberg

Lindén

et al. 2006

Journal of Lipid Research

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Adipose differentiation-related protein (ADRP) is a lipid droplet-associated protein that is expressed in various tissues. In mice treated with the peroxisome proliferatoractivated receptor a (PPARa) agonist Wy14,643 (Wy), hepatic mRNA and protein levels of ADRP as well as hepatic triglyceride content increased. Also in primary mouse hepatocytes, Wy increased ADRP expression and intracellular triglyceride mass. The triglyceride mass increased in spite of unchanged triglyceride biosynthesis and increased palmitic acid oxidation. However, Wy incubation decreased the secretion of newly synthesized triglycerides, whereas apolipoprotein B secretion increased. Thus, decreased availability of triglycerides for VLDL assembly could help to explain the cellular accumulation of triglycerides after Wy treatment. We hypothesized that this effect could be mediated by increased ADRP expression. Similar to PPARa activation, adenovirusmediated ADRP overexpression in mouse hepatocytes enhanced cellular triglyceride mass and decreased the secretion of newly synthesized triglycerides. In ADRP-overexpressing cells, Wy incubation resulted in a further decrease in triglyceride secretion. This effect of Wy was not attributable to decreased cellular triglycerides after increased fatty acid oxidation because the triglyceride mass in Wy-treated ADRPoverexpressing cells was unchanged. In summary, PPARa activation prevents the availability of triglycerides for VLDL assembly and increases hepatic triglyceride content in part by increasing the expression of ADRP. Peroxisome proliferator-activated receptor a (PPARa) is a ligand-activated transcription factor that plays a key role in the regulation of genes involved in carbohydrate, lipid, and lipoprotein metabolism (for review, see 1).PPARa is highly expressed in tissues with high mitochondrial and peroxisomal b-oxidation activities, such as liver, heart, kidney, and skeletal muscle (2-5). In humans, treatment with PPARa agonists (i.e., fibrates) results in decreased plasma levels of triglycerides and increased plasma HDL cholesterol levels (6, 7). The triglyceride-lowering effect of fibrates is partly explained by increased lipoprotein lipase expression (8) and downregulation of hepatic apolipoprotein C-III expression (9, 10), which results in increased turnover of VLDL. In addition, fibrates have been shown to decrease the plasma concentration of atherogenic small dense LDL particles (11, 12), indicating decreased hepatic triglyceride secretion, because small dense LDLs are products of triglyceride-rich VLDL (VLDL 1 ) particles (13). Indeed, fibrates have been shown to decrease VLDL triglyceride secretion in both humans and rats (14,15). In primary rat hepatocytes, fibrates reduced triglyceride secretion and decreased the size of the secreted apolipoprotein B (apoB)-containing lipoproteins (16). The reduced triglyceride secretion may be explained by decreased triglyceride biosynthesis in rat hepatocytes (16,17). However, in vivo in rats, incorporation of palmitate into liver triglyc...

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“…Many factors have been reported to be able to regulate apoB mRNA editing in the rodent liver or hepatic cells. In addition to the developmental stage (15,39), interventions such as growth hormones, estrogen, thyroid hormones, insulin, fasting, carbohydrate refeeding, treatment with ethanol, modulation of calcium concentration, and phosphorylation status affect editing (8,9,12,14,27,30). However, the exact molecular mechanisms that regulate apoB mRNA editing activity remain largely unclear.…”

mentioning

confidence: 99%

ApoB mRNA editing is mediated by a coordinated modulation of multiple apoB mRNA editing enzyme components

Chen

Eggerman²,

Patterson³

2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Chen Z, Eggerman TL, Patterson AP. ApoB mRNA editing is mediated by a coordinated modulation of multiple apoB mRNA editing enzyme components. Am J Physiol Gastrointest Liver Physiol 292: G53-G65, 2007. First published August 17, 2006; doi:10.1152/ajpgi.00118.2006.-Apolipoprotein (apo)B mRNA editing is accomplished by a large multiprotein complex. How these proteins interact to achieve the precise single-nucleotide change induced by this complex remains unclear. We investigated the relationship between altered apoB mRNA editing and changes in editing enzyme components to evaluate their roles in editing regulation. In the mouse fetal small intestine, we found that the dramatic developmental upregulation of apoB mRNA editing from ϳ3% to 88% begins with decreased levels of inhibitory CUG binding protein 2 (CUGBP2) expression followed by increased levels of apoB mRNA editing enzyme (apobec)-1 and apobec-1 complementation factor (ACF) (4-and 8-fold) and then by decreased levels of the inhibitory components glycine-arginine-tyrosine-rich RNA binding protein (GRY-RBP) and heterogeneous nuclear ribonucleoprotein (hnRNP)-C1 (75% and 56%). In contrast, the expression of KH-type splicing regulatory protein (KSRP), apobec-1 binding protein (ABBP)1, ABBP2, and Bcl-2-associated athanogene 4 (BAG4) were unaltered. In the human intestinal cell line Caco-2, the increase of apoB mRNA editing from ϳ1.7% to ϳ23% was associated with 6-and 3.2-fold increases of apobec-1 and CUGBP2, respectively. In the mouse large intestine, the editing was 48% and had a 2.7-fold relatively greater CUGBP2 level. Caco-2 and the large intestine thus have increased instead of decreased CUGBP2 and a lower level of editing, suggesting that inhibitory CUGBP2 may play a critical role in the magnitude of editing regulation. Short interfering RNA-mediated gene-specific knockdown of CUGBP2, GRY-RBP, and hnRNP-C1 resulted in increased editing in Caco-2 cells, consistent with their known inhibitory function. These data suggest that a coordinated expression of editing components determines the magnitude and specificity of apoB mRNA editing. apolipoprotein; development; apolipoprotein B mRNA editing enzyme; apolipoprotein B mRNA editing enzyme-1 complementation factor; CUG binding protein-2 APOLIPOPROTEIN B (apoB) plays a central role in lipoprotein metabolism (40). ApoB protein exists mainly in two isoforms: apoB-48 and apoB-100. Only synthesized by the intestine in the human, apoB-48 is essential for the assembly of chylomicrons and has an obligatory role in the intestinal absorption of dietary fats. ApoB-100, which is produced in the liver in humans, is required for the synthesis and secretion of VLDL (40). ApoB-100 is virtually the only protein component of LDLs, which are metabolic products of VLDL and contain about two-thirds of the cholesterol in human plasma. Elevated concentrations of apoB-100 and LDL-cholesterol in plasma are recognized risk factors for developing atherosclerotic coronary artery disease (40).ApoB-48 is generated by the editing of apoB mR...

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Direct effects of growth hormone on production and secretion of apolipoprotein B from rat hepatocytes

Cited by 30 publications

References 51 publications

Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver

Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver

PPARα activation increases triglyceride mass and adipose differentiation-related protein in hepatocytes

ApoB mRNA editing is mediated by a coordinated modulation of multiple apoB mRNA editing enzyme components

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