Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) regulates triglyceride metabolism by activation of the nuclear receptor FXR

Zhang, Yanqiao; Castellani, Lawrence W.; Sinal, Christopher J.; Gonzalez, Frank J.; Edwards, Peter A.

doi:10.1101/gad.1138104

Cited by 325 publications

(264 citation statements)

References 50 publications

(83 reference statements)

Supporting

Mentioning

252

Contrasting

Unclassified

Order By: Relevance

“…Moreover, independent of SREBP-1c, LXR directly activates other lipogenic genes including fatty acid synthase (FAS) [105]. In contrast, FXR transcription is increased in the fasting liver by the peroxisome proliferator activated receptor  coactivator 1 (PGC-1) [106]. The interaction between FXR and PGC-1 results in an induction of genes that promote triglyceride clearance and fatty acid -oxidation concomitantly with a reduction of -16 -lipogenic gene transcription [106].…”

Section: Nr1i Subfamily Members Regulate Lipid Levels In the Livermentioning

confidence: 99%

“…In contrast, FXR transcription is increased in the fasting liver by the peroxisome proliferator activated receptor  coactivator 1 (PGC-1) [106]. The interaction between FXR and PGC-1 results in an induction of genes that promote triglyceride clearance and fatty acid -oxidation concomitantly with a reduction of -16 -lipogenic gene transcription [106]. Among the FXR-target genes, SHP is the major inhibitor of SREBP-1c induction by LXRs [107].…”

Section: Nr1i Subfamily Members Regulate Lipid Levels In the Livermentioning

confidence: 99%

See 1 more Smart Citation

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Handschin¹,

Meyer²

2005

Archives of Biochemistry and Biophysics

156

105

View full text Add to dashboard Cite

Cloning and characterization of the orphan nuclear receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) led to major breakthroughs in studying drug-mediated transcriptional induction of drugmetabolizing cytochromes P450 (CYP). More recently, additional roles for CAR and PXR have been discovered. As examples, these xenosensors are involved in the homeostasis of cholesterol, bile acids, bilirubin and other endogenous hydrophobic molecules in the liver: CAR and PXR thus form an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the cholesterol-sensing liver X receptor (LXR, NR1H2/3) and the bileacid-activated farnesoid X receptor (FXR, NR1H4). In this review, functional interactions between these nuclear receptors as well as the consequences on physiology and pathophysiology of the liver are discussed.Key Words: nuclear receptors; drug-induction; lipids; bile acids; cholesterol; CAR; PXR; LXR; FXR; cytochrome P450 -4 -Metabolism of drugs and other xenobiotics in the liver is our body's primary defense against accumulation of potentially toxic, lipophilic compounds. The superfamily of cytochromes P450 (CYPs) are the best-studied class of enzymes in this task [1]. Transcriptional and post-transcriptional regulation of CYPs after exposure to certain drugs or other xenobiotics has been described several decades ago. Classically, the barbiturate phenobarbital induces its own metabolism and excretion by elevating CYP levels [2]. However, the molecular mechanisms underlying this observation remained a conundrum until the discovery and subsequent characterization of the constitutive androstane receptor (CAR, official nomenclature NR1I3) and the pregnane X receptor (PXR, NR1I2, alternatively called PAR or SXR), two members of the superfamily of nuclear receptors [3][4][5][6][7]. Mice with genetic ablations of CAR and PXR have significantly reduced inducibility of CYPs by a variety of drugs [8,9]. Whereas these two receptors share some common ligands and also have an overlapping target gene pattern [10][11][12][13], the mode of activation for CAR and PXR is quite different [14]. PXR is located in the nucleus, it has a low basal activity and is highly activated upon ligand binding [14,15]. In contrast, in the non-induced state, CAR resides in the cytoplasm. After treatment with activators such as phenobarbital, CAR shuttles to the nucleus to activate its target genes. Moreover, CAR localization and activity is regulated by various protein phosphorylation events [16][17][18]. For a more detailed discussion of CAR and PXR functions in drug-mediated induction of CYPs, see some recent reviews (e.g. refs. [19-23] and references therein).-5 - The nuclear receptor NR1I group includes xenosensors and lipid-sensing membersCompounds that induce transcription of CYPs and that activate CAR and PXR are structurally very diverse [21]. However, most of them are small in size and are highly lipophilic [24]. Whereas the CAR ligand-binding domain stru...

show abstract

Section: Nr1i Subfamily Members Regulate Lipid Levels In the Livermentioning

confidence: 99%

Section: Nr1i Subfamily Members Regulate Lipid Levels In the Livermentioning

confidence: 99%

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Handschin¹,

Meyer²

2005

Archives of Biochemistry and Biophysics

156

105

View full text Add to dashboard Cite

show abstract

“…Primary hepatocytes were isolated and maintained in DMEM (25 mM glucose)͞10% FBS (FBS) or 10% charcoalstripped FBS (18).…”

Section: Methodsmentioning

confidence: 99%

“…1B). We and others have previously proposed that the repression of SREBP-1c by GW4064 results in reduced hepatic triglyceride synthesis and plasma triglyceride levels (18,19).…”

Section: Activation Of Fxr By Gw4064 Lowers Plasma Glucose Levels Inmentioning

confidence: 99%

“…Studies using FXR Ϫ/Ϫ mice and FXR agonists have demonstrated a critical role for FXR in maintaining cholesterol and bile acid homeostasis as a result of the regulation of hepatic genes controlling both the catabolism of cholesterol to bile acids and the subsequent secretion of bile acids into the bile (13)(14)(15)(16). In addition, activation of FXR lowers plasma triglyceride levels (15,17) by a mechanism that involves the repression of hepatic SREBP-1c expression (18,19).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice

Zhang

Lee

Barrera

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

812

707

View full text Add to dashboard Cite

Farnesoid X receptor (FXR) plays an important role in maintaining bile acid and cholesterol homeostasis. Here we demonstrate that FXR also regulates glucose metabolism. Activation of FXR by the synthetic agonist GW4064 or hepatic overexpression of constitutively active FXR by adenovirus-mediated gene transfer significantly lowered blood glucose levels in both diabetic db͞db and wild-type mice. Consistent with these data, FXR null mice exhibited glucose intolerance and insulin insensitivity. We further demonstrate that activation of FXR in db͞db mice repressed hepatic gluconeogenic genes and increased hepatic glycogen synthesis and glycogen content by a mechanism that involves enhanced insulin sensitivity. In view of its central roles in coordinating regulation of both glucose and lipid metabolism, we propose that FXR agonists are promising therapeutic agents for treatment of diabetes mellitus.glucose ͉ GW4064 ͉ farnesoid X receptor-VP16 ͉ triglyceride ͉ cholesterol

show abstract

CREB3 mediates the transcriptional regulation of PGC‐1α, a master regulator of energy homeostasis and mitochondrial biogenesis

Locke,

Campbell,

2024

FEBS Letters

View full text Add to dashboard Cite

Lipid metabolism hinges on a balance between lipogenesis and fatty acid oxidation (FAO). Disruptions in this balance can induce endoplasmic reticulum (ER) stress triggering the unfolded protein response (UPR) and contribute to metabolic diseases. The UPR protein, Luman or CREB3, has recently been implicated in metabolic regulation–CREB3 knockout mice exhibit resistance to diet‐induced obesity and altered insulin sensitivity. Here, we show that CREB3 activated PPARGC1A transcription from a 1 kb promoter region. An increase in CREB3 expression correlated inversely with endogenous PPARGC1A mRNA levels and genes involved in FAO. As PGC‐1α encoded by PPARGC1A is a master regulator of mitochondrial biogenesis and energy homeostasis, these findings demonstrate that CREB3 is a transcriptional regulator of PGC‐1α, underlining the potential role of CREB3 in energy metabolism.

show abstract

Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) regulates triglyceride metabolism by activation of the nuclear receptor FXR

Cited by 325 publications

References 50 publications

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice

CREB3 mediates the transcriptional regulation of PGC‐1α, a master regulator of energy homeostasis and mitochondrial biogenesis

Contact Info

Product

Resources

About