Gestational dietary betaine supplementation suppresses hepatic expression of lipogenic genes in neonatal piglets through epigenetic and glucocorticoid receptor-dependent mechanisms

2016 ◽  
Vol 1861 (1) ◽  
pp. 41-50 ◽  
Author(s):  
Demin Cai ◽  
Junjian Wang ◽  
Yimin Jia ◽  
Haoyu Liu ◽  
Mengjie Yuan ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Hepatic Expression ◽  
Neonatal Piglets ◽  
Lipogenic Genes ◽  
Betaine Supplementation

scholarly journals Maternal dietary betaine supplementation modifies hepatic expression of cholesterol metabolic genes via epigenetic mechanisms in newborn piglets

2014 ◽  
Vol 112 (9) ◽  
pp. 1459-1468 ◽  
Author(s):  
Demin Cai ◽  
Yimin Jia ◽  
Jingyu Lu ◽  
Mengjie Yuan ◽  
Shiyan Sui ◽  
...  
Keyword(s):  
Mrna Level ◽  
Cholesterol Content ◽  
Epigenetic Mechanisms ◽  
Hepatic Cholesterol ◽  
Hepatic Expression ◽  
Neonatal Piglets ◽  
Protein Levels ◽  
Newborn Piglets ◽  
Metabolic Genes ◽  
Betaine Supplementation

To elucidate the effects of maternal dietary betaine supplementation on hepatic expression of cholesterol metabolic genes in newborn piglets and the involved epigenetic mechanisms, we fed gestational sows with control or betaine-supplemented diets (3 g/kg) throughout pregnancy. Neonatal piglets born to betaine-supplemented sows had higher serum methionine concentration and hepatic content of betaine, which was associated with significantly up-regulated hepatic expression of glycine N-methyltransferase. Prenatal betaine exposure increased hepatic cholesterol content and modified the hepatic expression of cholesterol metabolic genes in neonatal piglets. Sterol regulatory element-binding protein 2 was down-regulated at both mRNA and protein levels, while 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) was down-regulated at the mRNA level, but up-regulated at the protein level, in betaine-exposed piglets. The transcriptional repression of HMGCR was associated with CpG island hypermethylation and higher repressive histone mark H3K27me3 (histone H3 lysine 27 trimethylation) on the promoter, whereas increased HMGCR protein content was associated with significantly decreased expression of miR-497. Furthermore, LDL receptor was significantly down-regulated at both mRNA and protein levels in the liver of betaine-exposed piglets, which was associated with promoter CpG hypermethylation. In addition, the expression of cholesterol-27α-hydroxylase (CYP27α1) was up-regulated at both mRNA and protein levels, while the expression of cholesterol-7α-hydroxylase (CYP7α1) was increased at the mRNA level, but unchanged at the protein level associated with increased expression of miR-181. These results indicate that maternal betaine supplementation increases hepatic cholesterol content in neonatal piglets through epigenetic regulations of cholesterol metabolic genes, which involve alterations in DNA and histone methylation and in the expression of microRNA targeting these genes.

scholarly journals Maternal betaine supplementation during gestation modifies hippocampal expression of GR and its regulatory miRNAs in neonatal piglets

2016 ◽  
Vol 78 (6) ◽  
pp. 921-928 ◽  
Author(s):  
Qinwei SUN ◽  
Xi LI ◽  
Yimin JIA ◽  
Shifeng PAN ◽  
Runsheng LI ◽  
...  
Keyword(s):  
Neonatal Piglets ◽  
Betaine Supplementation

scholarly journals Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia

2014 ◽  
Vol 111 (10) ◽  
pp. 3817-3822 ◽  
Author(s):  
Ananda Chapagain ◽  
Paul W. Caton ◽  
Julius Kieswich ◽  
Petros Andrikopoulos ◽  
Nanda Nayuni ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Signaling ◽  
Hydroxysteroid Dehydrogenase ◽  
Metabolic Disturbances ◽  
Intracellular Regeneration ◽  
Rat Models ◽  
Hepatic Expression ◽  
Lipogenic Genes ◽  
Subtotal Nephrectomy

Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11βHSD1−/− mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.

scholarly journals Uteroplacental insufficiency alters hepatic expression, phosphorylation, and activity of the glucocorticoid receptor in fetal IUGR rats

2005 ◽  
Vol 289 (5) ◽  
pp. R1348-R1353 ◽  
Author(s):  
Mariana Baserga ◽  
Merica A. Hale ◽  
Robert A. McKnight ◽  
Xing Yu ◽  
Christopher W. Callaway ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Glucocorticoid Receptor ◽  
Chromatin Structure ◽  
P53 Protein ◽  
Mrna Levels ◽  
Artery Ligation ◽  
Pregnant Rat ◽  
Hepatic Expression ◽  
Protein Levels

Uteroplacental insufficiency (UPI) induces persistent changes in hepatic gene expression secondary to altered chromatin dynamics in the intrauterine growth- restricted (IUGR) rat liver. The glucocorticoid receptor (GR) is a transcription factor that when activated can induce changes in chromatin structure. To begin the process of identifying pathways by which IUGR affects chromatin structure, we hypothesized that UPI in the rat induces a significant increase in endogenous glucocorticoids (corticosterone) and increases GR expression and activation. To prove our hypothesis, we induced IUGR through bilateral uterine artery ligation of the pregnant rat. At day 1, UPI significantly increased corticosterone levels and was associated with increased total GR mRNA and protein levels in the liver, as well as increased hepatic phosphorylation of GR serine 211. Moreover, cyclin-dependent kinase 2 (CDK2) cyclinA/CDK2 protein levels, which selectively phosphorylate GR serine 211, were also significantly increased. To assess activity of the GR, we measured protein levels of the transcription factor p53 whose levels are downregulated, at least in part, by active GR. In this study, UPI decreased p53 protein and its downstream target Bax mRNA levels. We conclude that UPI in rats affects GR expression and activity in the liver. We speculate that these alterations early in life may contribute to the changes in chromatin structure and gene expression previously described in the IUGR liver.

scholarly journals Betaine Supplementation in Maternal Diet Modulates the Epigenetic Regulation of Hepatic Gluconeogenic Genes in Neonatal Piglets

PLoS ONE ◽  
2014 ◽  
Vol 9 (8) ◽  
pp. e105504 ◽  
Author(s):  
Demin Cai ◽  
Yimin Jia ◽  
Haogang Song ◽  
Shiyan Sui ◽  
Jingyu Lu ◽  
...  
Keyword(s):  
Epigenetic Regulation ◽  
Maternal Diet ◽  
Neonatal Piglets ◽  
Betaine Supplementation

scholarly journals Hepatocyte nuclear factor 4a and glucocorticoid receptor coordinately regulate lipid metabolism in mice fed a high-fat-high-sugar diet

2021 ◽  
Author(s):  
Hong Lu ◽  
Xiaohong Lei ◽  
Shangdong Guo ◽  
Rebecca Winkler ◽  
Savio John ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Fatty Liver ◽  
Knockout Mice ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
High Fat ◽  
Down Regulation ◽  
Lipogenic Genes ◽  
Catabolic Genes ◽  
Reporter Assays

ABSTRACTHepatocyte nuclear factor 4α (HNF4α) and glucocorticoid receptor (GR), master regulators of liver metabolism, are down-regulated in fatty liver diseases. The present study was aimed to elucidate the role of down-regulation of HNF4α and GR in fatty liver and hyperlipidemia. Adult mice with liver-specific heterozygote and knockout (knockout) of HNF4α were fed a low-fat diet (LFD) or a high-fat-high-sugar diet (HFHS) for 15 days. Compared to LFD-fed mice, HFHS-fed wildtype mice had hepatic induction of lipid catabolic genes and down-regulation of lipogenic genes. Compared to HFHS-fed wildtype mice, HNF4α heterozygote mice had down-regulation of lipid catabolic genes, induction of lipogenic genes, and increased hepatic and blood levels of lipids, whereas HNF4α knockout mice had mild hypolipidemia, down-regulation of lipid-efflux genes, but induction of genes for uptake/storage of lipids. Sterol-regulatory-element-binding protein-1c (SREBP-1C), a master lipogenic regulator, was induced in HFHS-fed HNF4α heterozygote mice. In reporter assays, HNF4α potently inhibited the transactivation of mouse and human SREBP-1C promoter by liver X receptor. Surprisingly, nuclear GR proteins were gene-dosage-dependently decreased in HNF4α heterozygote and knockout mice. HFHS-fed mice with liver-specific knockout of GR had increased hepatic lipids and induction of SREBP-1C and PPARγ. In reporter assays, GR and HNF4α synergistically/additively induced lipid catabolic genes. Phosphorylation of AMP-activated protein kinase (AMPK), a key GR modulator, was dramatically decreased in HNF4α knockout mice. Thus, cooperative induction of lipid catabolic genes and suppression of lipogenic genes by HNF4α and GR, modulated by AMPK, may mediate the early resistance to HFHS-induced fatty liver and hyperlipidemia.

Maternal Obesogenic Diet Regulates Offspring Bile Acid Homeostasis and Hepatic Lipid Metabolism via the Gut Microbiome in Mice

2022 ◽  
Author(s):  
Michael D. Thompson ◽  
Jisue Kang ◽  
Austin Faerber ◽  
Holly Hinrichs ◽  
Oguz Ozler ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Bile Acid ◽  
Mrna Expression ◽  
16S Sequencing ◽  
Hepatic Expression ◽  
Lipogenic Genes ◽  
Triglyceride Accumulation ◽  
High Fructose ◽  
Obesogenic Diet ◽  
Donor Offspring

Mice exposed in gestation to maternal high fat/high sucrose (HF/HS) diet develop altered bile acid (BA) homeostasis. We hypothesized that these reflect an altered microbiome and asked if microbiota transplanted from HF/HS offspring change hepatic BA and lipid metabolism to determine the directionality of effect. Female mice were fed HF/HS or chow (CON) for 6 weeks and bred with lean males. 16S sequencing was performed to compare taxa in offspring. Cecal microbiome transplantation (CMT) was performed from HF/HS or CON offspring into antibiotic treated mice fed chow or high fructose. BA, lipid metabolic, and gene expression analyses performed in recipient mice. Gut microbiomes from HF/HS offspring segregated from CON offspring, with increased Firmicutes to Bacteriodetes ratios and Verrucomicrobial abundance. Following CMT, HF/HS recipient mice had larger BA pools, and increased intrahepatic muricholic acid and decreased deoxycholic acid species. HF/HS recipient mice exhibited downregulated hepatic Mrp2, increased hepatic Oatp1b2, and decreased ileal Asbt mRNA expression. HF/HS recipient mice exhibited decreased cecal butyrate and increased hepatic expression of Il6. HF/HS recipient mice had larger livers, and increased intrahepatic triglyceride versus CON recipient mice after fructose feeding, with increased hepatic mRNA expression of lipogenic genes including Srebf1, Fabp1, Mogat1, and Mogat2. CMT from HF/HS offspring increased BA pool and shifted the composition of the intrahepatic BA pool. CMT from HF/HS donor offspring increased fructose-induced liver triglyceride accumulation. These findings support a causal role for vertical transfer of an altered microbiome in hepatic BA and lipid metabolism in HF/HS offspring.

The effect of maternal intake of sucrose or high-fructose corn syrup (HFCS)-55 during gestation and lactation on lipogenic gene expression in rat offspring at 3 and 12 weeks of age

2018 ◽  
Vol 9 (5) ◽  
pp. 481-486 ◽  
Author(s):  
H. Kaur ◽  
C. R. Toop ◽  
B. S. Muhlhausler ◽  
S. Gentili
Keyword(s):  
Messenger Rna ◽  
Binding Protein ◽  
Hepatic Metabolism ◽  
Perinatal Exposure ◽  
High Fructose Corn Syrup ◽  
Corn Syrup ◽  
Hepatic Expression ◽  
Lipogenic Genes ◽  
High Fructose ◽  
Element Binding Protein

AbstractPerinatal exposure to sucrose or high-fructose corn syrup-55 (HFCS-55) in rats has previously been associated with altered hepatic fat content and composition post-weaning, although the effects on hepatic metabolism are unknown. The current study aimed to determine the sex-specific effects of maternal consumption of sucrose or HFCS-55 on the expression of hepatic lipogenic genes in the offspring. Liver samples were collected from offspring of albino Wistar rats provided with ad libitum access to either water (control), 10% sucrose or 10% HFCS-55 solution during pregnancy and lactation at 3 weeks (control n=16, sucrose n=22, HFCS-55 n=16) and 12 weeks (control n=16, sucrose n=10, HFCS-55 n=16) of age. Hepatic expression of the transcription factors such as carbohydrate response element-binding protein, sterol regulatory element-binding protein-1c and downstream genes was determined by quantitative real-time PCR. Sucrose-exposed offspring had higher hepatic SREBP-1c messenger RNA expression compared with control and HFCS-55 groups at both 3 weeks (P=0.01) and 12 weeks (P=0.03) of age. There were no differences in the expression of other hepatic lipogenic genes between groups at either 3 or 12 weeks. Thus, perinatal exposure to sucrose may be more detrimental to offspring hepatic metabolism compared with HFCS-55, independent of sex, and it will be important to evaluate the longer-term effects of perinatal sucrose exposure in future studies.

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