Citrulline and Nonessential Amino Acids Prevent Fructose-Induced Nonalcoholic Fatty Liver Disease in Rats.
Study Goal
The researchers aimed to compare the effects of Citrulline and an isonitrogenous mixture of nonessential amino acids on fructose-induced nonalcoholic fatty liver disease (NAFLD) in rats.
Results Summary
Citrulline effectively prevented fructose-induced NAFLD, correcting metabolic disturbances, improving Arg bioavailability, and normalizing gene expression related to lipid metabolism. Both Citrulline and NEAAs restored liver function, but Citrulline uniquely restored Fas gene expression and Arg bioavailability to control levels.
Population
Male Sprague Dawley rats
Effective Dosage
1 g · kg(-1) · d(-1)
Duration
8 weeks
Interactions
None mentioned
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
fructose diet | increase | NAFLD | male Sprague Dawley rats | - | led to | #1 |
fructose diet | increase | visceral fat mass | male Sprague Dawley rats | 128% | significantly higher | #2 |
fructose diet | decrease | lean body mass | male Sprague Dawley rats | -7% | lower | #3 |
fructose diet | increase | insulin resistance | male Sprague Dawley rats | 135% | led to | #4 |
fructose diet | increase | plasma triglycerides (TGs) | male Sprague Dawley rats | 67% | increased | #5 |
fructose diet | decrease | Arg bioavailability | male Sprague Dawley rats | -27% | decreased | #6 |
fructose diet | increase | gene expression of fatty acid synthase (Fas) | male Sprague Dawley rats | 2-fold | caused a 2-fold increase | #7 |
fructose diet | decrease | gene expression of carnitine palmitoyl-transferase 1a and microsomal TG transfer protein | male Sprague Dawley rats | 70% and 90% | 70% and 90% decreases | #8 |
fructose diet | increase | gene expression of sterol regulatory element-binding protein-1c (Srebp1c) and carbohydrate-responsive element-binding protein (Chrebp) | male Sprague Dawley rats | nearly 10-fold | nearly 10-fold higher | #9 |
fructose diet | decrease | gene expression of peroxisome proliferator-activated receptor α (Ppara) | male Sprague Dawley rats | 90% | 90% lower | #10 |
NEAA supplementation | neutral | fructose-induced NAFLD and associated metabolic alterations | male Sprague Dawley rats | - | corrected | #11 |
Cit supplementation | neutral | fructose-induced NAFLD and associated metabolic alterations | male Sprague Dawley rats | - | corrected | #12 |
NEAA supplementation | no change | Ppara gene expression | male Sprague Dawley rats | similar to controls | led to a Ppara gene expression similar to controls | #13 |
Cit supplementation | no change | Ppara gene expression | male Sprague Dawley rats | similar to controls | led to a Ppara gene expression similar to controls | #14 |
NEAA supplementation | decrease | gene expression of Srebp1c and Chrebp | male Sprague Dawley rats | 50-60% | decreased | #15 |
Cit supplementation | decrease | gene expression of Srebp1c and Chrebp | male Sprague Dawley rats | 50-60% | decreased | #16 |
Cit supplementation | no change | Fas gene expression | male Sprague Dawley rats | similar to controls | led to Fas gene expression similar to controls | #17 |
Cit supplementation | no change | Arg bioavailability | male Sprague Dawley rats | similar to controls | led to Arg bioavailability similar to controls | #18 |
Cit | neutral | fructose-induced NAFLD | male Sprague Dawley rats | - | effectively prevented | #19 |
NEAAs | neutral | fructose-induced NAFLD | male Sprague Dawley rats | - | effectively prevented | #20 |
BACKGROUND: Fructose induces nonalcoholic fatty liver disease (NAFLD). Citrulline (Cit) may exert a beneficial effect on steatosis. OBJECTIVE: We compared the effects of Cit and an isonitrogenous mixture of nonessential amino acids (NEAAs) on fructose-induced NAFLD. METHODS: Twenty-two male Sprague Dawley rats were randomly assigned into 4 groups (n = 4-6) to receive for 8 wk a 60% fructose diet, either alone or supplemented with Cit (1 g · kg(-1) · d(-1)), or an isonitrogenous amount of NEAAs, or the same NEAA-supplemented diet with starch and maltodextrin instead of fructose (controls). Nutritional and metabolic status, liver function, and expression of genes of hepatic lipid metabolism were determined. RESULTS: Compared with controls, fructose led to NAFLD with significantly higher visceral fat mass (128%), lower lean body mass (-7%), insulin resistance (135%), increased plasma triglycerides (TGs; 67%), and altered plasma amino acid concentrations with decreased Arg bioavailability (-27%). This was corrected by both NEAA and Cit supplementation. Fructose caused a 2-fold increase in the gene expression of fatty acid synthase (Fas) and 70% and 90% decreases in that of carnitine palmitoyl-transferase 1a and microsomal TG transfer protein via a nearly 10-fold higher gene expression of sterol regulatory element-binding protein-1c (Srebp1c) and carbohydrate-responsive element-binding protein (Chrebp), and a 90% lower gene expression of peroxisome proliferator-activated receptor α (Ppara). NEAA or Cit supplementation led to a Ppara gene expression similar to controls and decreased those of Srebp1c and Chrebp in the liver by 50-60%. Only Cit led to Fas gene expression and Arg bioavailability similar to controls. CONCLUSION: In our rat model, Cit and NEAAs effectively prevented fructose-induced NAFLD. On the basis of literature data and our findings, we propose that NEAAs may exert their effects specifically on the liver, whereas Cit presumably acts at both the hepatic and whole-body level, in part via improved peripheral Arg metabolism.