Abrogation of hepatic ATP-citrate lyase protects against fatty liver and ameliorates hyperglycemia in leptin receptor-deficient mice

Abstract

Hepatic steatosis is a hallmark of nonalcoholic fatty liver disease (NAFLD) and a key component of obesity-associated metabolic dysfunctions featuring dyslipidemia, insulin resistance, and loss of glycemic control. It has yet to be completely understood how much dysregulated de novo lipogenesis contributes to the pathogenic development of hepatic steatosis and insulin resistance. ATP-citrate lyase (ACL) is a lipogenic enzyme that catalyzes the critical reaction linking cellular glucose catabolism and lipogenesis, converting cytosolic citrate to acetyl-coenzyme A (CoA). Acetyl-CoA is further converted to malonyl-CoA, the essential precursor for fatty acid biosynthesis. We investigated whether dysregulation of hepatic ACL is metabolically connected to hepatic steatosis, insulin resistance, and hyperglycemia. We found that in leptin receptor-deficient db/db mice, the expression of ACL was selectively elevated in the liver but not in the white adipose tissue. Liver-specific ACL abrogation via adenovirus-mediated RNA interference prominently reduced the hepatic contents of both acetyl-CoA and malonyl-CoA, markedly inhibited hepatic de novo lipogenesis, and protected against hepatic steatosis in db/db mice. Surprisingly, liver-specific ACL abrogation markedly inhibited the expression of peroxisome proliferator-activated receptorgamma and the entire lipogenic program in the liver. Moreover, hepatic ACL deficiency resulted in significantly down-regulated expression of gluconeogenic genes in the liver as well as enhanced insulin sensitivity in the muscle, leading to substantially improved systemic glucose metabolism. Conclusion: These findings establish a crucial role of hepatic ACL in lipid and glucose metabolism; therefore, hepatic ACL may serve as a potential target to treat NAFLD and type 2 diabetes.

Gene Expression in Livers of BALB/C and C57BL/6J Mice Fed a High-Fat Diet

“…ACLY catalyzes the cleavage of citrate to oxaloacetate and acetyl-CoA, releasing acetyl-CoA, which can then be used in fatty acid biosynthesis in the extramitochondrial cytosol (Botham and Mayes 2006). In leptin receptor-deficient db/db mice where hepatic ACLY is abnormally elevated, targeted suppression of ACLY in the liver can correct obesityassociated fatty liver (Wang et al 2009). FASN catalyzes the last step in fatty acid biosynthesis and thus is believed to be a major determinant of the maximal hepatic capacity to generate fatty acids by de novo lipogenesis (Dorn et al 2010).…”

ATP-Citrate Lyase Reduction Mediates Palmitate-induced Apoptosis in Pancreatic Beta Cells

“…On one hand, elevated cellular lipid synthesis might be expected to have deleterious effects over the long term. For example, reducing ACLY activity in liver was recently shown to protect against hepatic steatosis (56). On the other hand, de novo lipid synthesis is essential for many cellular functions.…”

Fibroblast Growth Factor 21 Is Regulated by the IRE1α-XBP1 Branch of the Unfolded Protein Response and Counteracts Endoplasmic Reticulum Stress-induced Hepatic Steatosis

“…Adenoviruses for XBP1s overexpression and knockdown were the generous gifts from Dr. Ling Qi (Cornell University). The knockdown control adenovirus Ad-sh-LacZ was generated as described with the BLOCK-iT adenoviral RNAi expression system (Invitrogen) in HEK293A cells according to the manufacturer's instructions (48). For infection of mouse primary hepatocytes, viruses were used at a multiplicity of infection of 40, which was measured according to the manufacturer's instructions.…”