Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2.
Hepatic steatosis is a core feature of the metabolic syndrome and type 2 diabetes and leads to hepatic insulin resistance. Malonyl-CoA, generated by acetyl-CoA carboxylases 1 and 2 (Acc1 and Acc2), is a key regulator of both mitochondrial fatty acid oxidation and fat synthesis. We used a diet-induced rat model of nonalcoholic fatty liver disease (NAFLD) and hepatic insulin resistance to explore the impact of suppressing Acc1, Acc2, or both Acc1 and Acc2 on hepatic lipid levels and insulin sensitivity. While suppression of Acc1 or Acc2 expression with antisense oligonucleotides (ASOs) increased fat oxidation in rat hepatocytes, suppression of both enzymes with a single ASO was significantly more effective in promoting fat oxidation. Suppression of Acc1 also inhibited lipogenesis whereas Acc2 reduction had no effect on lipogenesis. In rats with NAFLD, suppression of both enzymes with a single ASO was required to significantly reduce hepatic malonyl-CoA levels in vivo, lower hepatic lipids (long-chain acyl-CoAs, diacylglycerol, and triglycerides), and improve hepatic insulin sensitivity. Plasma ketones were significantly elevated compared with controls in the fed state but not in the fasting state, indicating that lowering Acc1 and -2 expression increases hepatic fat oxidation specifically in the fed state. These studies suggest that pharmacological inhibition of Acc1 and -2 may be a novel approach in the treatment of NAFLD and hepatic insulin resistance.
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
David B
DB
Savage
Cheol Soo
CS
Choi
Varman T
VT
Samuel
Zhen-Xiang
ZX
Liu
Dongyan
D
Zhang
Amy
A
Wang
Xian-Man
XM
Zhang
Gary W
GW
Cline
Xing Xian
XX
Yu
John G
JG
Geisler
Sanjay
S
Bhanot
Brett P
BP
Monia
Gerald I
GI
Shulman
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D004032:Diet; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy* / Q000201:enzymology*; D022781:Hepatocytes / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D014280:Triglycerides / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D016376:Oligonucleotides, Antisense; D014280:Triglycerides; C498191:Acacb protein, mouse; D000103:Acetyl-CoA Carboxylase