Prevention of Lipid Peroxidation–derived Cyclic DNA Adduct and Mutation in High-Fat Diet–induced Hepatocarcinogenesis by Theaphenon E

Abstract

Obesity is associated with cancer risk and its link with liver cancer is particularly strong. Obesity causes non-alcoholic fatty liver disease (NAFLD) that could progress to hepatocellular carcinoma (HCC). Chronic inflammation likely plays a key role. We carried out a bioassay in the high-fat diet (HFD)-fed C57BL/6J mice to provide insight into the mechanisms of obesity-related HCC by studying γ-OHPdG, a mutagenic DNA adduct derived from lipid peroxidation. In an 80-week bioassay, mice received a low-fat diet (LFD), high-fat diet (HFD), and HFD with 2% Theaphenon E (TE) (HFD+TE). HFD mice developed a 42% incidence of HCC and LFD mice a 16%. Remarkably, TE, a standardized green tea extract formulation, completely blocked HCC in HFD mice with a 0% incidence. γ-OHPdG measured in the hepatic DNA of mice fed HFD and HFD+TE showed its levels increased during the early stages of NAFLD in HFD mice and the increases were significantly suppressed by TE, correlating with the tumor data. Whole-exome sequencing showed an increased mutation load in the liver tumors of HFD mice with G>A and G>T as the predominant mutations, consistent with the report that γ-OHPdG induces G>A and G>T. Furthermore, the mutation loads were significantly reduced in HFD+TE mice, particularly G>T, the most common mutation in human HCC. These results demonstrate in a relevant model of obesity-induced HCC that γ-OHPdG formation during fatty liver disease may be an initiating event for accumulated mutations that leads to HCC and this process can be effectively inhibited by TE. .

High-Fat Diet–Induced Functional and Pathologic Changes in Lacrimal Gland

“…This response occurred on a HFD based on rises in reactive oxygen species levels and lipid peroxidation. 34,35 Oxidative stress is a key factor determining the progression of numerous systemic diseases. 36e38 In the current study, it is evident that the HFD activated inflammatory signaling pathways based on increases in inflammatory cell infiltration, and this response is a known indicator of oxidative stress.…”

Ablation of sphingosine kinase 2 suppresses fatty liver-associated hepatocellular carcinoma via downregulation of ceramide transfer protein

“…The HFHSD model recapitulates the development of spontaneous HCC in NAFLD livers and enables a focus on the underlying lipid metabolic causes. Long-term exposure to an HFHSD leads to liver tumors in mice with varied incidence rates up to 68.8% [ 32 – 35 ]. We identified visible liver tumors and neoplastic lesions in 35.7% of WT mice (Fig.…”

Epigallocatechin Gallate Induces Hepatic Stellate Cell Senescence and Attenuates Development of Hepatocellular Carcinoma

“…This includes reversibility of mutation load that is caused by DEN. In a high-fat diet (HFD) mouse model of HCC, Theaphenon E (TE), a standardized green tea extract formulation, blocked HCC formation via prevention of lipid peroxidation-derived mutagenic cyclic DNAadduct (γ-OHPdG) formation resulting in decreased mutation load particularly G>T, the most common mutation in human HCC [51]. Consistent with these results, TE reduced HCC incidence in xeroderma pigmentosum group A knockout mice and DEN-injected mice and the reduction in HCC incidence was associated with decreased (γ-OHPdG) levels [52].…”