title: 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 receptor-gamma 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Chinese Academy of Sciences, the Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.forename: Shoufeng
authors.initials: S
authors.lastname: Li
authors.forename: Yue
authors.initials: Y
authors.lastname: Yu
authors.forename: Jia
authors.initials: J
authors.lastname: You
authors.forename: Rong
authors.initials: R
authors.lastname: Zeng
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Liangyou
authors.initials: L
authors.lastname: Rui
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000378:metabolism*; D000105:Acetyl Coenzyme A / Q000096:biosynthesis; D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005234:Fatty Liver / Q000378:metabolism* / Q000517:prevention & control; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006943:Hyperglycemia / Q000378:metabolism*; D007333:Insulin Resistance; D050356:Lipid Metabolism; D050155:Lipogenesis; D008099:Liver / Q000201:enzymology; D008297:Male; D008316:Malonyl Coenzyme A / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D054411:Receptors, Leptin / Q000172:deficiency*
chemical_list: D005230:Fatty Acids, Nonesterified; D054411:Receptors, Leptin; D008316:Malonyl Coenzyme A; D000105:Acetyl Coenzyme A; D001275:ATP Citrate (pro-S)-Lyase; D005947:Glucose