RGD Reference Report - Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis. - Rat Genome Database

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Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis.

Authors: Yamaguchi, K  Yang, L  McCall, S  Huang, J  Yu, XX  Pandey, SK  Bhanot, S  Monia, BP  Li, YX  Diehl, AM 
Citation: Yamaguchi K, etal., Hepatology. 2008 Feb;47(2):625-35.
RGD ID: 10400849
Pubmed: PMID:18000880   (View Abstract at PubMed)
DOI: DOI:10.1002/hep.21988   (Journal Full-text)

Retinyl ester (RE) stores decrease during hepatic stellate cell (HSC) activation and liver fibrosis. Although retinol esterification is mostly catalyzed by lecithin:retinol acyltransferase (LRAT), diacylglycerol acyltransferase (DGAT)1 also does this. In previous reports, LRAT(-/-) mice had reduced hepatic RE but neither excessive HSC activation nor liver fibrosis, and DGAT1(-/-) mice had increased liver levels of RE and retinol. We sought to clarify the role of DGAT1 in liver fibrosis. Expression of DGAT1/2 was compared by real time PCR in freshly isolated, primary mouse HSCs and hepatocytes. To induce nonalcoholic steatohepatitis (NASH) and liver fibrosis, adult male db/db mice were fed methionine choline-deficient (MCD) diets. Half were treated with DGAT1 antisense oligonucleotide (ASO); the rest were injected with saline. Results were compared with chow-fed controls. Inhibition of DGAT1 in liver had no effect on hepatic triglyceride content or liver necroinflammation but reduced HSC activation and liver fibrosis in mice with NASH. To evaluate the role of DGAT1 in HSC activation, HSC were isolated from healthy rats treated with DGAT1 ASO or saline. DGAT1 was expressed at relatively high levels in HSCs. HSC isolated from DGAT1 ASO-treated rats had reduced DGAT1 expression and increased messenger RNA (mRNA) levels of LRAT and cellular retinol binding protein-1. During culture, they retained more vitamin A, had repressed collagen a2 (I) transcriptional activity, and expressed less collagen a1 (I) and a2 (I) mRNA. CONCLUSION: DGAT1 may be a therapeutic target in NASH because inhibiting DGAT1 favorably altered. HSC retinoid homeostasis and inhibited hepatic fibrosis in mice with NASH.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
liver cirrhosis treatmentISODgat1 (Mus musculus)10400849; 10400849associated with Non-alcoholic Fatty Liver DiseaseRGD 
liver cirrhosis treatmentIMP 10400849associated with Non-alcoholic Fatty Liver DiseaseRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of hepatic stellate cell activation  IMP 10400849 RGD 
regulation of vitamin A metabolic process  IMP 10400849 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Dgat1  (diacylglycerol O-acyltransferase 1)

Genes (Mus musculus)
Dgat1  (diacylglycerol O-acyltransferase 1)

Genes (Homo sapiens)
DGAT1  (diacylglycerol O-acyltransferase 1)


Additional Information