RGD Reference Report - Effect of Creosote Bush-Derived NDGA on Expression of Genes Involved in Lipid Metabolism in Liver of High-Fructose Fed Rats: Relevance to NDGA Amelioration of Hypertriglyceridemia and Hepatic Steatosis. - Rat Genome Database

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Effect of Creosote Bush-Derived NDGA on Expression of Genes Involved in Lipid Metabolism in Liver of High-Fructose Fed Rats: Relevance to NDGA Amelioration of Hypertriglyceridemia and Hepatic Steatosis.

Authors: Zhang, Haiyan  Li, Yihang  Hu, Jie  Shen, Wen-Jun  Singh, Madhurima  Hou, Xiaoming  Bittner, Alex  Bittner, Stefanie  Cortez, Yuan  Tabassum, Juveria  Kraemer, Fredric B  Azhar, Salman 
Citation: Zhang H, etal., PLoS One. 2015 Sep 22;10(9):e0138203. doi: 10.1371/journal.pone.0138203. eCollection 2015.
RGD ID: 329955565
Pubmed: PMID:26394137   (View Abstract at PubMed)
PMCID: PMC4578927   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0138203   (Journal Full-text)

Nordihydroguaiaretic acid (NDGA), the main metabolite of Creosote bush, has been shown to have profound effects on the core components of the metabolic syndrome (MetS), lowering blood glucose, free fatty acids (FFA) and triglyceride (TG) levels in several models of dyslipidemia, as well as improving body weight (obesity), insulin resistance, diabetes and hypertension, and ameliorating hepatic steatosis. In the present study, a high-fructose diet (HFrD) fed rat model of hypertriglyceridemia was employed to further delineate the underlying mechanism by which NDGA exerts its anti-hypertriglyceridemic action. In the HFrD treatment group, NDGA administration by oral gavage decreased plasma levels of TG, glucose, FFA, and insulin, increased hepatic mitochondrial fatty acid oxidation and attenuated hepatic TG accumulation. qRT-PCR measurements indicated that NDGA treatment increased the mRNA expression of key fatty acid transport (L-FABP, CD36), and fatty acid oxidation (ACOX1, CPT-2, and PPARα transcription factor) genes and decreased the gene expression of enzymes involved in lipogenesis (FASN, ACC1, SCD1, L-PK and ChREBP and SREBP-1c transcription factors). Western blot analysis indicated that NDGA administration upregulated hepatic insulin signaling (P-Akt), AMPK activity (P-AMPK), MLYCD, and PPARα protein levels, but decreased SCD1, ACC1 and ACC2 protein content and also inactivated ACC1 activity (increased P-ACC1). These findings suggest that NDGA ameliorates hypertriglyceridemia and hepatic steatosis primarily by interfering with lipogenesis and promoting increased channeling of fatty acids towards their oxidation.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Hypertriglyceridemia treatmentISOAcaca (Rattus norvegicus)329955565; 329955565 RGD 
Hypertriglyceridemia treatmentISOAcacb (Rattus norvegicus)329955565; 329955565 RGD 
Hypertriglyceridemia treatmentIEP 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565 RGD 
Hypertriglyceridemia treatmentISODgat2 (Rattus norvegicus)329955565; 329955565 RGD 
Hypertriglyceridemia treatmentISOFasn (Rattus norvegicus)329955565; 329955565 RGD 
Hypertriglyceridemia treatmentISOGpam (Rattus norvegicus)329955565; 329955565 RGD 
Hypertriglyceridemia treatmentISOMlxipl (Rattus norvegicus)329955565; 329955565 RGD 
Hypertriglyceridemia treatmentISOMlycd (Rattus norvegicus)329955565; 329955565 RGD 
Hypertriglyceridemia treatmentISOPklr (Rattus norvegicus)329955565; 329955565 RGD 
Hypertriglyceridemia treatmentISOPpargc1a (Rattus norvegicus)329955565; 329955565 RGD 
Hypertriglyceridemia treatmentISOPpargc1b (Rattus norvegicus)329955565; 329955565 RGD 
Hypertriglyceridemia treatmentISOScd (Rattus norvegicus)329955565; 329955565 RGD 
Hypertriglyceridemia treatmentISOSrebf1 (Rattus norvegicus)329955565; 329955565 RGD 
Hypertriglyceridemia treatmentISOXbp1 (Rattus norvegicus)329955565; 329955565 RGD 
Insulin Resistance treatmentISOAcaca (Rattus norvegicus)329955565; 329955565 RGD 
Insulin Resistance treatmentISOAcacb (Rattus norvegicus)329955565; 329955565 RGD 
Insulin Resistance treatmentIEP 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565 RGD 
Insulin Resistance treatmentISODgat2 (Rattus norvegicus)329955565; 329955565 RGD 
Insulin Resistance treatmentISOFasn (Rattus norvegicus)329955565; 329955565 RGD 
Insulin Resistance treatmentISOGpam (Rattus norvegicus)329955565; 329955565 RGD 
Insulin Resistance treatmentISOMlxipl (Rattus norvegicus)329955565; 329955565 RGD 
Insulin Resistance treatmentISOMlycd (Rattus norvegicus)329955565; 329955565 RGD 
Insulin Resistance treatmentISOPklr (Rattus norvegicus)329955565; 329955565 RGD 
Insulin Resistance treatmentISOPpargc1a (Rattus norvegicus)329955565; 329955565 RGD 
Insulin Resistance treatmentISOPpargc1b (Rattus norvegicus)329955565; 329955565 RGD 
Insulin Resistance treatmentISOScd (Rattus norvegicus)329955565; 329955565 RGD 
Insulin Resistance treatmentISOSrebf1 (Rattus norvegicus)329955565; 329955565 RGD 
Insulin Resistance treatmentISOXbp1 (Rattus norvegicus)329955565; 329955565 RGD 
metabolic dysfunction-associated steatotic liver disease treatmentISOAcaca (Rattus norvegicus)329955565; 329955565 RGD 
metabolic dysfunction-associated steatotic liver disease treatmentISOAcacb (Rattus norvegicus)329955565; 329955565 RGD 
metabolic dysfunction-associated steatotic liver disease treatmentIEP 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565 RGD 
metabolic dysfunction-associated steatotic liver disease treatmentISODgat2 (Rattus norvegicus)329955565; 329955565 RGD 
metabolic dysfunction-associated steatotic liver disease treatmentISOFasn (Rattus norvegicus)329955565; 329955565 RGD 
metabolic dysfunction-associated steatotic liver disease treatmentISOGpam (Rattus norvegicus)329955565; 329955565 RGD 
metabolic dysfunction-associated steatotic liver disease treatmentISOMlxipl (Rattus norvegicus)329955565; 329955565 RGD 
metabolic dysfunction-associated steatotic liver disease treatmentISOMlycd (Rattus norvegicus)329955565; 329955565 RGD 
metabolic dysfunction-associated steatotic liver disease treatmentISOPklr (Rattus norvegicus)329955565; 329955565 RGD 
metabolic dysfunction-associated steatotic liver disease treatmentISOPpargc1a (Rattus norvegicus)329955565; 329955565 RGD 
metabolic dysfunction-associated steatotic liver disease treatmentISOPpargc1b (Rattus norvegicus)329955565; 329955565 RGD 
metabolic dysfunction-associated steatotic liver disease treatmentISOScd (Rattus norvegicus)329955565; 329955565 RGD 
metabolic dysfunction-associated steatotic liver disease treatmentISOSrebf1 (Rattus norvegicus)329955565; 329955565 RGD 
metabolic dysfunction-associated steatotic liver disease treatmentISOXbp1 (Rattus norvegicus)329955565; 329955565 RGD 

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
nordihydroguaiaretic acid decreases expression ISOAcaca (Rattus norvegicus)329955565; 329955565NDGA decreases expression of mRNA in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid increases phosphorylationISOAcaca (Rattus norvegicus)329955565; 329955565NDGA increases phosphorylation in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid decreases expression ISOAcacb (Rattus norvegicus)329955565; 329955565NDGA decreases expression of Acacb protein in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid increases expression ISOAcox1 (Rattus norvegicus)329955565; 329955565NDGA increases expression of mRNA in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid increases phosphorylationISOAkt1 (Rattus norvegicus)329955565; 329955565NDGA increases phosphorylation in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid decreases expression EXP 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565NDGA decreases expression of mRNA in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid increases phosphorylationEXP 329955565; 329955565; 329955565; 329955565; 329955565NDGA increases phosphorylation in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid decreases expression EXP 329955565NDGA decreases expression of Acacb protein in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid increases expression EXP 329955565; 329955565; 329955565; 329955565NDGA increases expression of mRNA in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid increases expression ISOCd36 (Rattus norvegicus)329955565; 329955565NDGA increases expression of mRNA in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid increases expression ISOCpt2 (Rattus norvegicus)329955565; 329955565NDGA increases expression of mRNA in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid decreases expression ISODgat2 (Rattus norvegicus)329955565; 329955565NDGA decreases expression of mRNA in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid increases expression ISOFabp2 (Rattus norvegicus)329955565; 329955565NDGA increases expression of mRNA in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid decreases expression ISOFasn (Rattus norvegicus)329955565; 329955565NDGA decreases expression of mRNA in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid decreases expression ISOGpam (Rattus norvegicus)329955565; 329955565NDGA decreases expression of mRNA in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid increases phosphorylationISOGsk3a (Rattus norvegicus)329955565; 329955565NDGA increases phosphorylation in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid increases phosphorylationISOGsk3b (Rattus norvegicus)329955565; 329955565NDGA increases phosphorylation in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid decreases expression ISOMlxipl (Rattus norvegicus)329955565; 329955565NDGA decreases expression of mRNA in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid increases expression ISOMlycd (Rattus norvegicus)329955565; 329955565NDGA increases expression of Mlycd protein in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid increases expression EXP 329955565NDGA increases expression of Mlycd protein in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid decreases expression ISOPklr (Rattus norvegicus)329955565; 329955565NDGA decreases expression of mRNA in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid increases expression ISOPpargc1a (Rattus norvegicus)329955565; 329955565NDGA increases expression of Ppara protein in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid increases phosphorylationISOPrkaa2 (Rattus norvegicus)329955565; 329955565NDGA increases phosphorylation in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid increases expression EXP 329955565NDGA increases expression of Ppara protein in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid decreases expression ISOScd (Rattus norvegicus)329955565; 329955565NDGA decreases expression of mRNA and protein in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid decreases expression ISOSrebf1 (Rattus norvegicus)329955565; 329955565NDGA decreases expression of mRNA in liver of high fructose fed ratsRGD 
nordihydroguaiaretic acid decreases expression EXP 329955565NDGA decreases expression of mRNA and protein in liver of high fructose fed ratsRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
response to nutrient  IEP 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565; 329955565 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Acaca  (acetyl-CoA carboxylase alpha)
Acacb  (acetyl-CoA carboxylase beta)
Acox1  (acyl-CoA oxidase 1)
Akt1  (AKT serine/threonine kinase 1)
Cd36  (CD36 molecule)
Cpt2  (carnitine palmitoyltransferase 2)
Dgat2  (diacylglycerol O-acyltransferase 2)
Fabp2  (fatty acid binding protein 2)
Fasn  (fatty acid synthase)
Gpam  (glycerol-3-phosphate acyltransferase, mitochondrial)
Gsk3a  (glycogen synthase kinase 3 alpha)
Gsk3b  (glycogen synthase kinase 3 beta)
Mlxipl  (MLX interacting protein-like)
Mlycd  (malonyl-CoA decarboxylase)
Pklr  (pyruvate kinase L/R)
Ppargc1a  (PPARG coactivator 1 alpha)
Ppargc1b  (PPARG coactivator 1 beta)
Prkaa2  (protein kinase AMP-activated catalytic subunit alpha 2)
Scd  (stearoyl-CoA desaturase)
Srebf1  (sterol regulatory element binding transcription factor 1)
Xbp1  (X-box binding protein 1)

Genes (Mus musculus)
Acaca  (acetyl-Coenzyme A carboxylase alpha)
Acacb  (acetyl-Coenzyme A carboxylase beta)
Acox1  (acyl-Coenzyme A oxidase 1, palmitoyl)
Akt1  (thymoma viral proto-oncogene 1)
Cd36  (CD36 molecule)
Cpt2  (carnitine palmitoyltransferase 2)
Dgat2  (diacylglycerol O-acyltransferase 2)
Fabp2  (fatty acid binding protein 2, intestinal)
Fasn  (fatty acid synthase)
Gpam  (glycerol-3-phosphate acyltransferase, mitochondrial)
Gsk3a  (glycogen synthase kinase 3 alpha)
Gsk3b  (glycogen synthase kinase 3 beta)
Mlxipl  (MLX interacting protein-like)
Mlycd  (malonyl-CoA decarboxylase)
Pklr  (pyruvate kinase liver and red blood cell)
Ppargc1a  (peroxisome proliferative activated receptor, gamma, coactivator 1 alpha)
Ppargc1b  (peroxisome proliferative activated receptor, gamma, coactivator 1 beta)
Prkaa2  (protein kinase, AMP-activated, alpha 2 catalytic subunit)
Scd1  (stearoyl-Coenzyme A desaturase 1)
Srebf1  (sterol regulatory element binding transcription factor 1)
Xbp1  (X-box binding protein 1)

Genes (Homo sapiens)
ACACA  (acetyl-CoA carboxylase alpha)
ACACB  (acetyl-CoA carboxylase beta)
ACOX1  (acyl-CoA oxidase 1)
AKT1  (AKT serine/threonine kinase 1)
CD36  (CD36 molecule (CD36 blood group))
CPT2  (carnitine palmitoyltransferase 2)
DGAT2  (diacylglycerol O-acyltransferase 2)
FABP2  (fatty acid binding protein 2)
FASN  (fatty acid synthase)
GPAM  (glycerol-3-phosphate acyltransferase, mitochondrial)
GSK3A  (glycogen synthase kinase 3 alpha)
GSK3B  (glycogen synthase kinase 3 beta)
MLXIPL  (MLX interacting protein like)
MLYCD  (malonyl-CoA decarboxylase)
PKLR  (pyruvate kinase L/R)
PPARGC1A  (PPARG coactivator 1 alpha)
PPARGC1B  (PPARG coactivator 1 beta)
PRKAA2  (protein kinase AMP-activated catalytic subunit alpha 2)
SCD  (stearoyl-CoA desaturase)
SREBF1  (sterol regulatory element binding transcription factor 1)
XBP1  (X-box binding protein 1)


Additional Information