title: The role of the carbohydrate response element-binding protein in male fructose-fed rats.
abstract: By 2030, nearly half of Americans will have nonalcoholic fatty liver disease. In part, this epidemic is fueled by the increasing consumption of caloric sweeteners coupled with an innate capacity to convert sugar into fat via hepatic de novo lipogenesis. In addition to serving as substrates, monosaccharides also increase the expression of key enzymes involved in de novo lipogenesis via the carbohydrate response element-binding protein (ChREBP). To determine whether ChREBP is a potential therapeutic target, we decreased hepatic expression of ChREBP with a specific antisense oligonucleotide (ASO) in male Sprague-Dawley rats fed either a high-fructose or high-fat diet. ChREBP ASO treatment decreased plasma triglyceride concentrations compared with control ASO treatment in both diet groups. The reduction was more pronounced in the fructose-fed group and attributed to decreased hepatic expression of ACC2, FAS, SCD1, and MTTP and a decrease in the rate of hepatic triglyceride secretion. This was associated with an increase in insulin-stimulated peripheral glucose uptake, as assessed by the hyperinsulinemic-euglycemic clamp. In contrast, ChREBP ASO did not alter hepatic lipid content or hepatic insulin sensitivity. Interestingly, fructose-fed rats treated with ChREBP ASO had increased plasma uric acid, alanine transaminase, and aspartate aminotransferase concentrations. This was associated with decreased expression of fructose aldolase and fructokinase, reminiscent of inherited disorders of fructose metabolism. In summary, these studies suggest that targeting ChREBP may prevent fructose-induced hypertriglyceridemia but without the improvements in hepatic steatosis and hepatic insulin responsiveness.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06536-8012, USA.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Erion
authors.forename: Violetta
authors.initials: V
authors.lastname: Popov
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Hsiao
authors.forename: Daniel
authors.initials: D
authors.lastname: Vatner
authors.forename: Kisha
authors.initials: K
authors.lastname: Mitchell
authors.forename: Shin
authors.initials: S
authors.lastname: Yonemitsu
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Nagai
authors.forename: Mario
authors.initials: M
authors.lastname: Kahn
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Gillum
authors.forename: Jianying
authors.initials: J
authors.lastname: Dong
authors.forename: Susan F
authors.initials: SF
authors.lastname: Murray
authors.forename: Vara Prasad
authors.initials: VP
authors.lastname: Manchem
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D005632:Fructose / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016376:Oligonucleotides, Antisense / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; C491898:Fas protein, rat; C442825:Mlxipl protein, rat; D016376:Oligonucleotides, Antisense; D014280:Triglycerides; D019014:fas Receptor; C106092:microsomal triglyceride transfer protein; D005632:Fructose; D013230:Stearoyl-CoA Desaturase; D000103:Acetyl-CoA Carboxylase