Back to Search
Start Over
SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease
- Source :
- International Journal of Molecular Medicine.
- Publication Year :
- 2008
- Publisher :
- Spandidos Publications, 2008.
-
Abstract
- Nonalcoholic fatty liver disease (NAFLD) is a common liver disease whose prevalence has increased markedly. We reported previously that fatty acid synthesis was enhanced in NAFLD with the accumulation of fatty acids. To clarify the disorder, we evaluated the expression of genes regulating fatty acid synthesis by real-time PCR using samples from NAFLD (n=22) and normal liver (control; n=10). A major regulator of fatty acids synthesis is sterol regulatory element-binding protein-1c (SREBP-1c). Its expression was significantly higher in NAFLD, nearly 5-fold greater than the controls. SREBP-1c is positively regulated by insulin signaling pathways, including insulin receptor substrate (IRS)-1 and -2. In NAFLD, IRS-1 expression was enhanced and correlated positively with SREBP-1c expression. In contrast, IRS-2 expression decreased by 50% and was not correlated with SREBP-1c. Forkhead box protein A2 (Foxa2) is a positive regulator of fatty acid oxidation and is itself negatively regulated by IRSs. Foxa2 expression increased in NAFLD and showed a negative correlation with IRS-2, but not with IRS-1, expression. It is known that SREBP-1c is negatively regulated by AMP-activated protein kinase (AMPK) but expression levels of AMPK in NAFLD were almost equal to those of the controls. These data indicate that, in NAFLD, insulin signaling via IRS-1 causes the up-regulation of SREBP1-c, leading to the increased synthesis of fatty acids by the hepatocytes; negative feedback regulation via AMPK does not occur and the activation of Foxa2, following a decrease of IRS-2, up-regulates fatty acid oxidation.
- Subjects :
- medicine.medical_specialty
Gene Expression
AMP-Activated Protein Kinases
Protein Serine-Threonine Kinases
Models, Biological
digestive system
Feedback
chemistry.chemical_compound
AMP-activated protein kinase
Multienzyme Complexes
Insulin receptor substrate
Internal medicine
Nonalcoholic fatty liver disease
Genetics
medicine
Humans
Insulin
fas Receptor
Beta oxidation
Fatty acid synthesis
Adaptor Proteins, Signal Transducing
DNA Primers
chemistry.chemical_classification
Base Sequence
biology
Reverse Transcriptase Polymerase Chain Reaction
Fatty Acids
Intracellular Signaling Peptides and Proteins
Fatty acid
AMPK
General Medicine
Phosphoproteins
medicine.disease
Fatty Liver
Insulin receptor
Endocrinology
Liver
chemistry
Case-Control Studies
Hepatocyte Nuclear Factor 3-beta
Insulin Receptor Substrate Proteins
biology.protein
Sterol Regulatory Element Binding Protein 1
Signal Transduction
Subjects
Details
- ISSN :
- 1791244X and 11073756
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Medicine
- Accession number :
- edsair.doi.dedup.....b6bd0882896a1ce5bb9ff02475ef0ca2