AICAR, an AMPK activator, has protective effects on alcohol-induced fatty liver in rats.
BACKGROUND
Previous work with metformin has shown that this antidiabetic agent improves nonalcoholic fatty liver in ob/ob mice. AMP-activated protein kinase (AMPK) is one of the major cellular regulators of lipid and glucose metabolism, and reportedly mediates the beneficial metabolic effects of metformin. In this study, we examined the effects of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), an AMPK activator, on an experimental model of ethanol-induced hepatic steatosis.


METHODS
Rats were randomly divided into three groups: (A) rats fed ethanol-containing liquid diet for six weeks; (B) rats pair-fed ethanol-containing liquid diet for six weeks, during the last three weeks of which they were subcutaneously injected with 0.5 mg AICAR/g body weight per day; (C) rats pair-fed isocaloric liquid diet without ethanol for six weeks. At the end of the six-week period, the animals were sacrificed. Serum and liver specimens were analyzed using biochemical and histologic methods, as well as real-time PCR.


RESULTS
Chronic ethanol feeding resulted in fatty liver both histologically and biochemically, whereas AICAR administration attenuated the degree of change in the liver. AICAR also decreased the hepatic sterol regulatory factor binding protein-1c (SREBP-1c) and reduced fatty acid synthase (FAS) expression; these changes led to reduced triglyceride synthesis in rat livers. Furthermore, detection of 4-hydroxy-2-nonenal (4-HNE)-protein adducts showed that the AICAR treatment also decreased the products of lipid peroxidation.


CONCLUSIONS
In this preclinical rat model, AICAR, an AMPK activator, appears to protect the liver from fatty changes associated with chronic alcohol use. As such, AICAR may have a role in the treatment and prevention of alcohol-induced fatty liver.
Tomita
Kengo
K
Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Tamiya
Gen
G
Ando
Satoshi
S
Kitamura
Naoto
N
Koizumi
Haruna
H
Kato
Shinzo
S
Horie
Yoshinori
Y
Kaneko
Takehiko
T
Azuma
Toshifumi
T
Nagata
Hiroshi
H
Ishii
Hiromasa
H
Hibi
Toshifumi
T
D055372:AMP-Activated Protein Kinases; D000447:Aldehydes / Q000494:pharmacology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D002492:Central Nervous System Depressants; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D020536:Enzyme Activators / Q000627:therapeutic use*; D000431:Ethanol; D064429:Fatty Acid Synthases / Q000096:biosynthesis; D005234:Fatty Liver / Q000139:chemically induced / Q000517:prevention & control*; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009097:Multienzyme Complexes / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012265:Ribonucleotides / Q000627:therapeutic use*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D000447:Aldehydes; D002492:Central Nervous System Depressants; D015853:Cysteine Proteinase Inhibitors; D020536:Enzyme Activators; D009097:Multienzyme Complexes; D012265:Ribonucleotides; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D000620:Aminoimidazole Carboxamide; D000431:Ethanol; D064429:Fatty Acid Synthases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; C027576:4-hydroxy-2-nonenal