Metronidazole enhances steatosis-related early-stage hepatocarcinogenesis in high fat diet-fed rats through DNA double-strand breaks and modulation of autophagy.
Ayumi EguchiSayaka MizukamiMisato NakamuraSousuke MasudaHirotada MurayamaMasashi KawashimaMari InohanaRei NagaharaMio KobayashiRisako YamashitaSuzuka UomotoEmi MakinoRyoichi OhtsukaNaofumi TakahashiShim-Mo HayashiRobert R MaronpotMakoto ShibutaniToshinori YoshidaPublished in: Environmental science and pollution research international (2021)
Nonalcoholic fatty liver disease is a hepatic disorder with deposition of fat droplets and has a high risk of progression to steatosis-related hepatitis and irreversible hepatic cancer. Metronidazole (MNZ) is an antiprotozoal and antimicrobial agent widely used to treat patients infected with anaerobic bacteria and intestinal parasites; however, MNZ has also been shown to induce liver tumors in rodents. To investigate the effects of MNZ on steatosis-related early-stage hepatocarcinogenesis, male rats treated with N-nitrosodiethylamine following 2/3 hepatectomy at week 3 were received a control basal diet, high fat diet (HFD), or HFD containing 0.5% MNZ. The HFD induced obesity and steatosis in the liver, accompanied by altered expression of Pparg and Fasn, genes related to lipid metabolism. MNZ increased nuclear translocation of lipid metabolism-related transcription factor peroxisome proliferator-activated receptor gamma in hepatocytes, together with altered liver expression of lipid metabolism genes (Srebf1, Srebf2, Pnpla2). Furthermore, MNZ significantly increased the number of preneoplastic liver foci, accompanied by DNA double-strand breaks and late-stage autophagy inhibition, as reflected by increased levels of γ-H2AX, LC3, and p62. Therefore, MNZ could induce steatosis-related hepatocarcinogenesis by inducing DNA double-strand breaks and modulating autophagy in HFD-fed rats.
Keyphrases
- high fat diet
- insulin resistance
- adipose tissue
- early stage
- signaling pathway
- transcription factor
- metabolic syndrome
- high fat diet induced
- type diabetes
- oxidative stress
- poor prognosis
- newly diagnosed
- chronic kidney disease
- cell free
- end stage renal disease
- weight loss
- endoplasmic reticulum stress
- cell death
- gene expression
- circulating tumor
- fatty acid
- staphylococcus aureus
- body mass index
- physical activity
- drug induced
- genome wide
- lymph node
- young adults
- study protocol
- patient reported outcomes
- weight gain
- liver injury