SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease.
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.
Kohjima
Motoyuki
M
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Higuchi
Nobito
N
Kato
Masaki
M
Kotoh
Kazuhiro
K
Yoshimoto
Tsuyoshi
T
Fujino
Tatsuya
T
Yada
Masayoshi
M
Yada
Ryoko
R
Harada
Naohiko
N
Enjoji
Munechika
M
Takayanagi
Ryoichi
R
Nakamuta
Makoto
M
D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001483:Base Sequence; D016022:Case-Control Studies; D017931:DNA Primers / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics*; D005246:Feedback; D015870:Gene Expression; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics*; D019014:fas Receptor / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; C491901:FAS protein, human; C496502:FOXA2 protein, human; D005227:Fatty Acids; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D010750:Phosphoproteins; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D019014:fas Receptor; D051542:Hepatocyte Nuclear Factor 3-beta; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases