Down-regulation of SREBP-1c is associated with the development of burned-out NASH.
OBJECTIVE
It is well-known that hepatic triglycerides (TG) diminish with the progression of non-alcoholic steatohepatitis (NASH), which has been designated as burned-out NASH, but its mechanism remains unclear. We aimed to explore the changes in hepatic fatty acid (FA) and TG metabolism with disease progression.


METHODS
Hepatic expression of key genes in healthy individuals (n=6) and patients with simple steatosis (SS, n=10), mild NASH (fibrosis stage 1-2, n=20), and advanced NASH (fibrosis stage 3-4, n=20) were assessed by quantitative polymerase chain reaction.


RESULTS
Hepatic expression of genes related to FA uptake and oxidation and very-low-density lipoprotein synthesis/export did not differ among the groups. However, the mRNA levels of sterol regulatory element-binding protein (SREBP)-1c and its downstream genes FA synthase, acetyl-coenzyme A carboxylase 1, and diacylglycerol acyltransferase 1 were inversely correlated with fibrosis stage. Immunoblot analysis revealed a remarkable reduction in mature SREBP-1c levels in advanced NASH. Furthermore, hepatic expression of tumor necrosis factor-alpha increased in accordance with fibrosis progression, which was possibly related to the decrease in hepatic SREBP-1c expression.


CONCLUSIONS
Down-regulation of SREBP-1c and lipogenic enzymes may be associated with the development of burned-out NASH.
Nagaya
Tadanobu
T
Department of Gastroenterology, Shinshu University School of Medicine, Japan. naopi@shinshu-u.ac.jp
Tanaka
Naoki
N
Suzuki
Takefumi
T
Sano
Kenji
K
Horiuchi
Akira
A
Komatsu
Michiharu
M
Nakajima
Takero
T
Nishizawa
Tomoko
T
Joshita
Satoru
S
Umemura
Takeji
T
Ichijo
Tetsuya
T
Matsumoto
Akihiro
A
Yoshizawa
Kaname
K
Nakayama
Jun
J
Tanaka
Eiji
E
Aoyama
Toshifumi
T
D000328:Adult; D016022:Case-Control Studies; D015536:Down-Regulation; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D012720:Severity of Illness Index; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics*; D014280:Triglycerides / Q000378:metabolism
D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides