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. 2006 Mar;116(3):817-24.
doi: 10.1172/JCI27300. Epub 2006 Feb 16.

Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2

David B Savage  1 , Cheol Soo Choi, Varman T Samuel, Zhen-Xiang Liu, Dongyan Zhang, Amy Wang, Xian-Man Zhang, Gary W Cline, Xing Xian Yu, John G Geisler, Sanjay Bhanot, Brett P Monia, Gerald I Shulman
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Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2

V体育ios版 - David B Savage et al. J Clin Invest. 2006 Mar.

Abstract

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 VSports手机版. .

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Figures

Figure 1
Figure 1
Acc ASOs decrease ACC expression and lower malonyl-CoA levels in rat liver. After 4 weeks of ASO treatment, total RNA was isolated from liver (A and B) and muscle (C and D), and gene expression (ACC1 mRNA [A and C] and ACC2 mRNA [B and D]) was then assessed by real-time RT-PCR. Hepatic Acc1 (265 kDA) and Acc2 (280 kDa) protein levels were assessed by Western blot analysis (E). Malonyl-CoA concentration was measured in liver homogenates from rats in the fed state (F). Data are expressed as mean values ± SEM of 4–6 rats per treatment group. Acc1&2, Acc1 and Acc2. *P < 0.05 versus ASOctrl treatment group.
Figure 2
Figure 2
Effect of Acc ASOs on fatty acid oxidation and TG synthesis in primary rat hepatocytes. (A) Fat oxidation. (B and C) TG synthesis was assayed in the presence (B) and absence (C) of exogenous fatty acid (oleate). Data are expressed as mean values ± SEM (n = 3). *P < 0.05; **P < 0.01.
Figure 3
Figure 3
Acc1 and -2 ASO therapy lowers hepatic lipid levels in rats. TG (A), LCCoAs (P = 0.13), (B) and DAG (C) levels. Plasma ketones (β-hydroxybutyrate [β-OHB]) are similar in control and Acc1 and -2 ASO–treated rats in the fasting state (D) but are significantly increased in Acc1 and -2–treated rats in the fed state (E). Data are expressed as mean values ± SEM of 4–6 rats per treatment group. *P < 0.05 versus ASOctrl treatment group.
Figure 4
Figure 4
Acc1 and -2 ASO treatment significantly improved hepatic insulin sensitivity in high-fat–fed rats. Peripheral and hepatic insulin sensitivity were assessed by means of hyperinsulinemic-euglycemic clamps (A–C). (A) Glucose infusion rates; (B) peripheral glucose turnover; (C) suppression of HGP during hyperinsulinemic-euglycemic clamps. Data are expressed as mean values ± SEM for 6–9 rats per treatment group. *P < 0.05 versus ASOctrl treatment group.
Figure 5
Figure 5
Acc1 and -2 ASO therapy improves hepatic insulin signaling. Acc1 and -2 ASO treatment does not alter basal HGP (A) but enhances insulin-mediated suppression of HGP in high-fat–fed rats (B). Reduced PKCε membrane translocation (C) may be directly involved in improving hepatic insulin signaling. This change is associated with increased Akt2 activity (D) and increased Foxo1 phosphorylation, which promotes nuclear exclusion of Foxo1, thereby lowering its transcriptional activity on the promoters of gluconeogenic genes, such as PEPCK and G6P. (D) Akt2 activity before (basal) and after 20 minutes insulin stimulation in ASOctrl and Acc1 and -2 ASO–treated rats. (E) Foxo1 phosphorylation was assessed before (basal) and after 20 minutes insulin stimulation by Western blotting using an antibody specific for serine256 phosphorylation. Data is expressed as the ratio of phosphorylated Foxo1 (Phos-Foxo1)/actin (loading control). (F) Suppression of hepatic PEPCK mRNA and (G) G6P mRNA expression during hyperinsulinemic-euglycemic clamps. *P < 0.05 versus ASOctrl treatment group. Data are expressed as mean values ± SEM for 4–6 rats per treatment group. *P < 0.05 versus ASOctrl treatment group.
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