scholarly journals Hepatocyte-specific Sirt6 deficiency impairs ketogenesis

2018 ◽  
Vol 294 (5) ◽  
pp. 1579-1589 ◽  
Author(s):  
Lei Chen ◽  
Qinhui Liu ◽  
Qin Tang ◽  
Jiangying Kuang ◽  
Hong Li ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Gene Promoter ◽  
Camp Response Element Binding ◽  
Hepatic Lipid Metabolism ◽  
Camp Response Element ◽  
Hepatic Lipid ◽  
Element Binding Protein ◽  
Regulate Lipid Metabolism

Sirt6 is an NADH (NAD+)-dependent deacetylase with a critical role in hepatic lipid metabolism. Ketogenesis is controlled by a signaling network of hepatic lipid metabolism. However, how Sirt6 functions in ketogenesis remains unclear. Here, we demonstrated that Sirt6 functions as a mediator of ketogenesis in response to a fasting and ketogenic diet (KD). The KD-fed hepatocyte-specific Sirt6 deficiency (HKO) mice exhibited impaired ketogenesis, which was due to enhanced Fsp27 (fat-specific induction of protein 27), a protein known to regulate lipid metabolism. In contrast, overexpression of Sirt6 in mouse primary hepatocytes promoted ketogenesis. Mechanistically, Sirt6 repressed Fsp27β expression by interacting with Crebh (cAMP response element–binding protein H) and preventing its recruitment to the Fsp27β gene promoter. The KD-fed HKO mice also showed exacerbated hepatic steatosis and inflammation. Finally, Fsp27 silencing rescued hypoketonemia and other metabolic phenotypes in KD-fed HKO mice. Our data suggest that the Sirt6–Crebh–Fsp27 axis is pivotal for hepatic lipid metabolism and inflammation. Sirt6 may be a pharmacological target to remedy metabolic diseases.

scholarly journals Estradiol Suppresses Phosphorylation of Cyclic Adenosine 3′,5′-Monophosphate Response Element Binding Protein (CREB) in the Pituitary: Evidence for Indirect Action via Gonadotropin-Releasing Hormone

1999 ◽  
Vol 13 (8) ◽  
pp. 1338-1352
Author(s):  
W. Rachel Duan ◽  
Jennifer L. Shin ◽  
J. Larry Jameson
Keyword(s):  
Gene Promoter ◽  
Camp Response Element Binding ◽  
Ovariectomized Rats ◽  
Pituitary Cells ◽  
Camp Response Element ◽  
Similar Reduction ◽  
Response Element ◽  
Creb Phosphorylation ◽  
Element Binding Protein ◽  
Phosphorylated Creb

Abstract Estradiol acts on the hypothalamus and pituitary gland to modulate the synthesis and secretion of gonadotropins. We recently reported that GnRH-induced transcription of the human gonadotropin α-gene promoter is increased markedly in transfected pituitary cells derived from animals treated with estradiol. Because the cAMP response element binding (CREB) protein plays an important role in the transcriptional regulation of this promoter and is highly regulated by posttranslational phosphorylation, we hypothesized that it might serve as a target for estradiol-induced sensitivity to GnRH. In this study, we assessed the roles of estradiol and GnRH in the regulation of CREB phosphorylation in the rat pituitary. Using an antibody that specifically recognizes phosphorylated CREB (pCREB), we found that the pituitary content of pCREB was inversely related to the level of estradiol during the estrous cycle. Ovariectomy increased the level of pCREB, and treatment with estradiol for 10 days decreased the content of pCREB dramatically (93% inhibition). A similar reduction of pCREB was seen when ovariectomized rats were treated with a GnRH receptor antagonist for 10 days. This result indicates that the ovariectomy-induced increase in pCREB is GnRH-dependent. In αT3 gonadotrope cells, estradiol had no direct effect on CREB phosphorylation, whereas GnRH increased CREB phosphorylation 4- to 5-fold within 5 min. We conclude that estradiol inhibits CREB phosphorylation in the gonadotrope, probably by inhibiting GnRH production. The estradiol-induced decrease in CREB phosphorylation is proposed to lower basalα -promoter activity and increase its responsiveness to GnRH. (Molecular Endocrinology 13: 1338–1352, 1999)

scholarly journals Perilipin 5 S155 phosphorylation by PKA is required for the control of hepatic lipid metabolism and glycemic control

2020 ◽  
pp. jlr.RA120001126
Author(s):  
Stacey N Keenan ◽  
William DeNardo ◽  
Jieqiong Lou ◽  
Ralf B. Schittenhelm ◽  
Magdalene K. Montgomery ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Glycemic Control ◽  
Fatty Acid Oxidation ◽  
Lipid Droplet ◽  
Critical Role ◽  
The Body ◽  
Acid Oxidation ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid

Perilipin (PLIN) 5 is a lipid droplet-associated protein that coordinates intracellular lipolysis in highly oxidative tissues and is thought to regulate lipid metabolism in response to phosphorylation by protein kinase A (PKA). We sought to identify PKA phosphorylation sites in PLIN5 and assess their functional relevance in cultured cells and the livers of mice. We detected phosphorylation on S155, S161 and S163 of recombinant PLIN5 by PKA in vitro and identified S155 as a functionally important site for lipid metabolism. Expression of phosphorylation-defective PLIN5 S155A in Plin5 null cells resulted in decreased rates of lipolysis and triglyceride-derived fatty acid oxidation compared with cells expressing wildtype PLIN5. These differences in lipid metabolism were not associated with differences in the cellular distribution of PLIN5. Rather, FLIM-FRET analysis of protein-protein interactions showed that PLIN5 S155 phosphorylation regulates PLIN5 interaction with adipose triglyceride lipase (ATGL) at the lipid droplet, but not with the co-activator of ATGL, α-β hydrolase domain-containing 5 (ABHD5). Re-expression of PLIN5 S155A in the liver of Plin5 liver-specific null mice reduced lipolysis when compared to mice with wildtype PLIN5 re-expression, but was not associated with other changes in hepatic lipid metabolism, such as fatty acid oxidation, de novo lipogenesis and triglyceride secretion. Furthermore, glycemic control was impaired in mice with expression of PLIN5 S155A compared with mice expressing PLIN5. Together, these studies demonstrate that PLIN5 S155 is required for PKA-mediated lipolysis and builds on the body of evidence demonstrating a critical role for PLIN5 in coordinating lipid and glucose metabolism

scholarly journals Prefrontal Cortex in Learning to Overcome Generalized Fear

2015 ◽  
Vol 9 ◽  
pp. JEN.S26227 ◽  
Author(s):  
Edward Korzus
Keyword(s):  
Prefrontal Cortex ◽  
Discrimination Learning ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Camp Response Element Binding ◽  
Normal Brain ◽  
Camp Response Element ◽  
Brain Functioning ◽  
Element Binding Protein

Normal brain functioning relies critically on the ability to control appropriate behavioral responses to fearful stimuli. Overgeneralized fear is the major symptom of anxiety disorders including posttraumatic stress disorder. This review describes recent data demonstrating that the medial prefrontal cortex (mPFC) plays a critical role in the refining of cues that drive the acquisition of fear response. Recent studies on molecular mechanisms that underlie the role of mPFC in fear discrimination learning are discussed. These studies suggest that prefrontal N-methyl-D-aspartate receptors expressed in excitatory neurons govern fear discrimination learning via a mechanism involving cAMP response element-binding protein-dependent engagement of acetyltransferase.

scholarly journals CREB (cAMP response element binding protein) and C/EBPα (CCAAT/enhancer binding protein) are required for the superstimulation of phosphoenolpyruvate carboxykinase gene transcription by adenoviral E1a and cAMP

2000 ◽  
Vol 352 (2) ◽  
pp. 335-342 ◽  
Author(s):  
John M. ROUTES ◽  
Lillester A. COLTON ◽  
Sharon RYAN ◽  
Dwight J. KLEMM
Keyword(s):  
Gene Transcription ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Binding Protein ◽  
Gene Promoter ◽  
Camp Response Element Binding ◽  
Dominant Negative ◽  
Camp Response Element ◽  
Response Element ◽  
Element Binding Protein ◽  
In Cells

In the present study, we observed superstimulated levels of cAMP-stimulated transcription from the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter in cells infected with wild-type adenovirus expressing 12S and 13S E1a proteins, or in cells expressing 13S E1a alone. cAMP-stimulated transcription was inhibited in cells expressing only 12S E1a, but slightly elevated in cells expressing E1a proteins with mutations in conserved regions 1 or 2, leading us to conclude that the superstimulation was mediated by conserved region 3 of 13S E1a. E1a failed to enhance cAMP-stimulated transcription from promoters containing mutations that abolish binding by cAMP response element binding protein (CREB) or CCAAT/enhancer binding proteins (C/EBPs). This result was supported by experiments in which expression of dominant-negative CREB and/or C/EBP proteins repressed E1a- and cAMP-stimulated transcription from the PEPCK gene promoter. In reconstitution experiments using a Gal4-responsive promoter, E1a enhanced cAMP-stimulated transcription when chimaeric Gal4–CREB and Gal4–C/EBPα were co-expressed. Phosphorylation of CREB on serine-133 was stimulated in cells treated with dibutyryl cAMP, whereas phosphorylation of C/EBPα was increased by E1a expression. Our data support a model in which cAMP agonists increase CREB activity and stimulate PEPCK gene transcription, a process that is enhanced by E1a through the phosphorylation of C/EBPα.

Regulation effects of rosemary (Rosmarinus officinalis Linn.) on hepatic lipid metabolism in OA induced NAFLD rats

2019 ◽  
Vol 10 (11) ◽  
pp. 7356-7365 ◽  
Author(s):  
Si-Jian Wang ◽  
Qian Chen ◽  
Meng-Yang Liu ◽  
Hai-Yang Yu ◽  
Jing-Qi Xu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Signaling Pathway ◽  
Rosmarinus Officinalis ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid ◽  
Regulate Lipid Metabolism ◽  
Effective Function

This paper first demonstrated that rosemary has an effective function to regulate lipid metabolism through the AMPK/SREBP1c signaling pathway in vivo and in vitro.

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