Polaprezinc attenuates liver fibrosis in a mouse model of non-alcoholic steatohepatitis.
OBJECTIVE
The effect of polaprezinc, a zinc-carnosine chelate compound, on the development of non-alcoholic steatohepatitis (NASH) was investigated in dietary methionine and choline deficient (MCD) mice.


METHODS
Mice were fed the MCD diet with or without polaprezinc (2.2 g/kg diet) for 10 weeks. Liver histopathology, triglyceride and lipid peroxide levels, and the expression of genes linked to fibrosis were then assessed.


RESULTS
MCD mice developed steatohepatitis accompanied by mild fibrosis with an increase in lipid peroxidation, hepatic stellate cell (HSC) activation, and the augmented mRNA expression of tumor necrosis factor-alpha, transforming growth factor-beta1 and procollagen alpha1(I). The mRNA expression levels of matrix metalloproteinase (MMP)-2 and tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 were also enhanced. Histopathologically, polaprezinc supplementation did not influence the development of steatosis but it apparently attenuated fibrosis. Polaprezinc slightly reduced lipid peroxidation and suppressed HSC activation as well as the mRNA expression of pro-inflammatory cytokines. Polaprezinc affected the MCD diet-enhanced expression of TIMP-1 even when administered relatively late.


CONCLUSIONS
These results suggest that polaprezinc attenuates fibrosis in NASH by reducing inflammation and lipid peroxidation and, during a later phase, promoting fibrolysis via the inhibition of TIMP expression in the liver. Further investigation is required to clarify the clinical efficacy of polaprezinc in patients with NASH.
Sugino
Haruko
H
Division of Pathophysiology, Center for Clinical Pharmacy and Clinical Sciences, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan. suginoh@pharm.kitasato-u.ac.jp
Kumagai
Naoki
N
Watanabe
Sakiko
S
Toda
Kyoko
K
Takeuchi
Osamu
O
Tsunematsu
Satoshi
S
Morinaga
Shojiroh
S
Tsuchimoto
Kanji
K
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002336:Carnosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002796:Choline Deficiency / Q000150:complications / Q000188:drug therapy; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017967:Zinc Compounds / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D009942:Organometallic Compounds; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D017967:Zinc Compounds; C061957:polaprezinc; D019716:Tissue Inhibitor of Metalloproteinase-2; D002336:Carnosine; D008715:Methionine; D000410:Alanine Transaminase; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse