Dietary fructose exacerbates hepatocellular injury when incorporated into a methionine-choline-deficient diet.
BACKGROUND
Methionine-choline-deficient (MCD) diets cause steatohepatitis in rodents and are used to model fatty liver disease in human beings. Recent studies have identified sucrose as a major contributor to MCD-related liver disease through its ability to promote hepatic de novo lipogenesis.


OBJECTIVE
To determine whether glucose and fructose, the two constitutents of sucrose, differ in their capacity to provoke steatohepatitis when incorporated individually into MCD formulas.


METHODS
MCD and control formulas prepared with either glucose or fructose as the sole source of carbohydrate were fed to mice for 21 days. Liver injury was assessed biochemically and histologically together with hepatic gene expression and fatty acid analysis.


RESULTS
Mice fed MCD formulas developed similar degrees of hepatic steatosis whether they contained glucose or fructose. By contrast, mice fed MCD-fructose developed significantly more hepatocellular injury than mice fed MCD-glucose, judged by histology, apoptosis staining and serum alanine aminotransferase. Liver injury in MCD-fructose mice coincided with an exaggerated rise in the ratio of long-chain saturated to unsaturated fatty acids in the liver. Notably, hepatic inflammation was not enhanced in mice fed MCD-fructose, correlating instead with hepatic lipid peroxidation, which was equivalent in the two MCD groups.


CONCLUSIONS
Fructose is more cytotoxic than glucose when used as the source of carbohydrate in MCD formulas.


CONCLUSIONS
The data suggest the enhanced cytotoxicity of fructose in the MCD model is related to its ability to stimulate de novo lipogenesis, which yields harmful long-chain saturated fatty acids.
Department of Pediatrics, University of California, San Francisco, CA, USA.
Michael K
MK
Pickens
Hisanobu
H
Ogata
Russell K
RK
Soon
James P
JP
Grenert
Jacquelyn J
JJ
Maher
D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose; D002784:Cholesterol / Q000097:blood; D002796:Choline Deficiency; D004032:Diet / Q000009:adverse effects*; D019422:Dietary Sucrose / Q000009:adverse effects*; D005234:Fatty Liver / Q000209:etiology* / Q000473:pathology; D005632:Fructose / Q000009:adverse effects*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000502:physiology; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008817:Mice, Mutant Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D019422:Dietary Sucrose; D014280:Triglycerides; D005632:Fructose; D002784:Cholesterol; D008715:Methionine; D000410:Alanine Transaminase