Alpha-lipoic acid decreases hepatic lipogenesis through adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways.
Fatty liver is common in obese subjects with insulin resistance. Hepatic expression of sterol regulatory element binding protein-1c (SREBP-1c), which plays a major role in hepatic steatosis, is regulated by multiple factors, including insulin, adenosine monophosphate-activated protein kinase (AMPK), liver X receptors (LXRs), and specificity protein 1. Alpha-lipoic acid (ALA), a naturally occurring antioxidant, has been shown to decrease lipid accumulation in skeletal muscle by activating AMPK. Here we show that ALA decreases hepatic steatosis and SREBP-1c expression in rats on a high fat diet or given an LXR agonist. ALA increased AMPK phosphorylation in the liver and in cultured liver cells, and dominant-negative AMPK partially prevented ALA-induced suppression of insulin-stimulated SREBP-1c expression. ALA also inhibited DNA-binding activity and transcriptional activity of both specificity protein 1 and LXR.


CONCLUSIONS
These results show that ALA prevents fatty liver disease through multiple mechanisms, and suggest that ALA can be used to prevent the development and progression of nonalcoholic fatty liver disease in patients with insulin resistance.
Park
Keun-Gyu
KG
Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.
Min
Ae-Kyung
AK
Koh
Eun Hee
EH
Kim
Hyoun Sik
HS
Kim
Mi-Ok
MO
Park
Hye-Sun
HS
Kim
Yong-Deuk
YD
Yoon
Tae-Seung
TS
Jang
Byoung Kuk
BK
Hwang
Jae Seok
JS
Kim
Jae Bum
JB
Choi
Hueng-Sik
HS
Park
Joong-Yeol
JY
Lee
In-Kyu
IK
Lee
Ki-Up
KU
D055372:AMP-Activated Protein Kinases; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005234:Fatty Liver / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007333:Insulin Resistance; D007700:Kinetics; D008055:Lipids / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008113:Liver Neoplasms; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D008063:Thioctic Acid / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism
D008055:Lipids; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D014280:Triglycerides; D008063:Thioctic Acid; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases