Reduction of liver fructokinase expression and improved hepatic inflammation and metabolism in liquid fructose-fed rats after atorvastatin treatment.
Consumption of beverages that contain fructose favors the increasing prevalence of metabolic syndrome alterations in humans, including non-alcoholic fatty liver disease (NAFLD). Although the only effective treatment for NAFLD is caloric restriction and weight loss, existing data show that atorvastatin, a hydroxymethyl-glutaryl-CoA reductase inhibitor, can be used safely in patients with NAFLD and improves hepatic histology. To gain further insight into the molecular mechanisms of atorvastatin's therapeutic effect on NAFLD, we used an experimental model that mimics human consumption of fructose-sweetened beverages. Control, fructose (10% w/v solution) and fructose+atorvastatin (30 mg/kg/day) Sprague-Dawley rats were sacrificed after 14 days. Plasma and liver tissue samples were obtained to determine plasma analytes, liver histology, and the expression of liver proteins that are related to fatty acid synthesis and catabolism, and inflammatory processes. Fructose supplementation induced hypertriglyceridemia and hyperleptinemia, hepatic steatosis and necroinflammation, increased the expression of genes related to fatty acid synthesis and decreased fatty acid β-oxidation activity. Atorvastatin treatment completely abolished histological signs of necroinflammation, reducing the hepatic expression of metallothionein-1 and nuclear factor kappa B binding. Furthermore, atorvastatin reduced plasma (x 0.74) and liver triglyceride (x 0.62) concentrations, decreased the liver expression of carbohydrate response element binding protein transcription factor (x 0.45) and its target genes, and increased the hepatic activity of the fatty acid β-oxidation system (x 1.15). These effects may be related to the fact that atorvastatin decreased the expression of fructokinase (x 0.6) in livers of fructose-supplemented rats, reducing the metabolic burden on the liver that is imposed by continuous fructose ingestion.
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Barcelona, Spain.
Laia
L
Vilà
Alba
A
Rebollo
Gunnar S
GS
Ađalsteisson
Marta
M
Alegret
Manuel
M
Merlos
Nuria
N
Roglans
Juan C
JC
Laguna
D000818:Animals; D000069059:Atorvastatin; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004040:Dietary Carbohydrates / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D005631:Fructokinases / Q000378:metabolism*; D005632:Fructose / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006505:Hepatitis / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015228:Hypertriglyceridemia / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D065626:Non-alcoholic Fatty Liver Disease; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004040:Dietary Carbohydrates; D005227:Fatty Acids; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; C442825:Mlxipl protein, rat; D016328:NF-kappa B; D011758:Pyrroles; D014280:Triglycerides; D005632:Fructose; D008668:Metallothionein; D000069059:Atorvastatin; D005631:Fructokinases; C046173:fructokinase; D017868:Cyclic AMP-Dependent Protein Kinases