[Therapeutic effects of insulin-sensitizing drugs on nonalcoholic fatty liver disease: experiment with rats].
OBJECTIVE
To investigate the therapeutic effects of insulin-sensitizing drugs, rosiglitazone and metformin, on nonalcoholic fatty liver disease (NAFLD).


METHODS
Forty-four male SD rats were randomized into 4 groups: normal control group (n = 8, fed with normal food) and NAFLD rats (n = 36, fed with high-fat food). Eight weeks later 4 rats were randomly selected from the NAFLD group and were killed to undergo pathological examination of the liver. When the establishment of experimental model of NAFLD rats was confirmed the remaining 32 NAFLD rats were subdivided into 4 equal subgroups: NAFLD control group (to be fed continuously with high-fat food), rosiglitazone treatment group (fed with normal food and rosiglitazone 1.5 mg x kg(-1) x d(-1) by gastric perfusion), metformin treatment group (fed with normal food and metformin 150 mg x kg(-1) x d(-1) by gastric perfusion), and dietary treatment group (fed with normal food and normal saline by gastric perfusion). By the end of the 12th week, all rats were killed to isolate the samples of serum to test the levels of total cholesterol (TC), triglyceride (TG), alanine transaminase (ALT), aspartate transaminase (AST), and tumor necrosis factor-alpha (TNF-alpha). Samples of liver tissue were taken to undergo pathology to examine fatty degeneration and inflammatory cell infiltration and detection of the levels of TC and TG. In the liver the weights of body and liver were measured so as to calculate the liver index.


RESULTS
(1) The levels of serum TC, TG, ALT, and AST, liver TC and TG, and liver index of the NAFLD control group increased significantly, and the liver histology of the NAFLD control group expressed moderate to severe fatty degeneration. (2) The serum TC levels of the rosiglitazone and metformin groups were 2.49 mmol/L +/- 0.68 mmol/L and 2.49 mmol/L +/- 0.58 mmol/L, both significantly lower than that of the NAFLD control group (4.55 mmol/L +/- 1.58 mmol/L, both P < 0.001). The serum TG levels of the rosiglitazone and metformin groups were 0.61 mmol/L +/- 0.17 mmol/L and 0.63 mmol/L +/- 0.16 mmol/L respectively, both significantly lower than that of the NAFLD control group (0.85 mmol/L +/- 0.15 mmol/L, both P < 0.001). The serum level of ALT of the rosiglitazone and metformin groups were 38.3 U/L +/- 10.6 U/L and 43.3 U/L +/- 27.5 U/L respectively, both significantly lower than that of the NAFLD control group (110.6 U/L +/- 44.2 U/L, P < 0.001 and P < 0.05). The serum levels of AST of the rosiglitazone and metformin groups were 141.7 U/L +/- 14.3 U/L and 174.5 U/L +/- 57.9 U/L, both significantly lower than that of the NAFLD control group (251.8 U/L +/- 91.0 U/L, both P < 0.05). The liver TG levels of the rosiglitazone and metformin groups were 18.9 mg/g +/- 2.7 mg/g and 20.4 mg/g +/- 3.6 mg/g respectively, both significantly lower than that of the NAFLD control group (54.8 mg/g +/- 7.6 mg/g, both P < 0.05). The fatty degeneration grades of liver tissues of the rosiglitazone and metformin groups were grade: 0.8 +/- 0.3 and 1.0 +/- 0.2, both significantly lower than that of the NAFLD control group (grade 2.8 +/- 0.5, both P < 0.05). The hepatic inflammation scores of: the rosiglitazone and metformin groups were 0.8 +/- 0.2 and 1.0 +/- 0.3 respectively, both significantly lower than that of the NAFLD control group (1.8 +/- 0.4, both P < 0.05). The levels of abnormality in serum TC and TG, liver TG, and liver histology of the dietary treatment group were all alleviated in comparison with the NAFLD control group, but were somewhat severer than those of the rosiglitazone and metformin treatment groups. (3) The serum TNF-alpha levels of the rosiglitazone and metformin treatment groups were 124.6 pg/mL +/- 21.0 pg/mL, 154.9 pg/mL +/- 32.5 pg/mL respectively, both significantly lower than that of the NAFLD group (324.2 pg/mL +/- 34.2 pg/mL, P < 0.001 and P < 0.05). The liver TNF-alpha levels of the rosiglitazone and metformin treatment groups were 0.24 +/- 0.14 and 0.30 +/- 0.12 respectively, both significantly lower than that of the NAFLD group (0.85 +/- 0.12, both P < 0.001). The levels of FAS mRNA expression of the rosiglitazone and metformin treatment groups were 0.22 +/- 0.14 and 0.29 +/- 0.16 respectively, both significantly lower than that of the NAFLD group (0.68 +/- 0.23, P < 0.001 and P < 0.005).


CONCLUSIONS
The insulin-sensitizing drugs, rosiglitazone and metformin, are effective in the treatment of NAFLD.
Zhang
Dong-mei
DM
Department of Gastrointestinal, Xiangya Hospital, Central South University, Changsha 410008, China.
Zhang
Gui-ying
GY
Wang
Tao
T
Zhong
Hui-ju
HJ
Chen
Wen-ke
WK
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002784:Cholesterol / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005234:Fatty Liver / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D015870:Gene Expression / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics
D004041:Dietary Fats; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D045162:Thiazolidinediones; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D000077154:Rosiglitazone; D008687:Metformin; D002784:Cholesterol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase