Epidemiology of non-alcoholic fatty liver disease and risk of hepatocellular carcinoma progression

Thandra, Krishna Chaitanya; Barsouk, Adam; Saginala, Kalyan; Aluru, John Sukumar; Rawla, Prashanth; Barsouk, Alexander

doi:10.5114/ceh.2020.102153

Cited by 23 publications

(9 citation statements)

References 55 publications

(74 reference statements)

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“…Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Although Hepatitis B virus (HBV) and hepatitis C virus (HCV) are still the top risk factors for HCC, a large percentage of HCC arises due to nonalcoholic fatty liver disease (NAFLD) ( El-Serag and Kanwal, 2014 ; Chaitanya Thandra et al, 2020 ). The prevalence of NAFLD is increasing because of the global epidemics of metabolic syndrome, a cluster of conditions including hypercholesterolemia, hypertension, hyperglycemia, obesity, and hypertriglyceridemia ( McGlynn et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Cholesterol Metabolism: A Double-Edged Sword in Hepatocellular Carcinoma

Zhou

Sun

2021

Front. Cell Dev. Biol.

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Hepatocellular carcinoma (HCC) represents a leading cause of cancer-related deaths globally. The rising incidence of metabolic syndrome and its hepatic manifestation, nonalcoholic fatty liver disease (NAFLD), have emerged as the fastest-growing cause of HCC in recent years. Cholesterol, a major lipid component of the cell membrane and lipoprotein particles, is primarily produced and metabolized by the liver. Numerous studies have revealed an increased cholesterol biosynthesis and uptake, reduced cholesterol exportation and excretion in HCC, which all contribute to lipotoxicity, inflammation, and fibrosis, known HCC risk factors. In contrast, some clinical studies have shown that higher cholesterol is associated with a reduced risk of HCC. These contradictory observations imply that the relationship between cholesterol and HCC is far more complex than initially anticipated. Understanding the role of cholesterol and deciphering the underlying molecular events in HCC development is highly relevant to developing new therapies. Here, we discuss the current understanding of cholesterol metabolism in the pathogenesis of NAFLD-associated HCC, and the underlying mechanisms, including the roles of cholesterol in the disruption of normal function of specific cell types and signaling transduction. We also review the clinical progression in evaluating the association of cholesterol with HCC. The therapeutic effects of lowering cholesterol will also be summarized. We also interpret reasons for the contradictory observations from different preclinical and human studies of the roles of cholesterol in HCC, aiming to provide a critical assessment of the potential of cholesterol as a therapeutic target.

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Section: Introductionmentioning

confidence: 99%

Cholesterol Metabolism: A Double-Edged Sword in Hepatocellular Carcinoma

Zhou

Sun

2021

Front. Cell Dev. Biol.

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“…Both NAFLD and atherosclerosis are inflammatory diseases with significant morbidity and mortality 26 , 27 . A better understanding of the mechanisms underlying NAFLD and atherosclerosis is important for developing more effective diagnostic and therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

Apigenin attenuates atherosclerosis and non-alcoholic fatty liver disease through inhibition of NLRP3 inflammasome in mice

Lü

Liu

Zhao

et al. 2023

Sci Rep

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Apigenin (APN), a flavone found in several plant foods with various biological properties such as anti-obesity, anti-inflammation and other abilities, alleviates atherosclerosis and non-alcoholic fatty liver disease (NAFLD) induced by a high fat diet (HFD) in mice. However, the underlying mechanisms have not been fully understood. In this study, we investigated the role of NLRP3 in anti-atherosclerosis and anti-NAFLD effect of APN in mouse models with NLRP3 deficiency. Atherosclerosis and NAFLD models were established by treatment of low density lipoprotein receptor-deficient (Ldlr−/−) mice and NLRP3−/− Ldlr−/− mice with a HFD diet (20% fat and 0.5% cholesterol) with or without APN. En face lipid accumulation analysis, plasma lipid levels, hepatic lipid accumulation and inflammation were analyzed and quantified. For in vitro experiments, HepG2 cells were stimulated by LPS plus oleic acid (OA) in the absence or presence of APN (50 μM). Lipid accumulation and the effect of APN on the NLRP3/NF-κB signaling pathway were investigated. APN administration partly reversed atherosclerosis and hepatic lipid accumulation, and decreased body weight and plasma lipid levels in Ldlr−/− mice when fed a HFD. Compared with Ldlr−/− mice, NLRP3−/− Ldlr−/− mice showed more severe atherosclerosis and hepatic lipid accumulation. Treating the HepG2 cells with APN reduced lipid accumulation. APN also inhibited activation of the NLRP3/ NF-κB signaling pathway stimulated by OA together with LPS. Our results indicate that APN supplementation prevents atherosclerosis and NAFLD via NLRP3 inhibition in mice, and suggest that APN might be a potential therapeutic agent for the prevention of atherosclerosis and NAFLD.

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“…While acetylation changes and HDAC expression changes are known in HCC 20 and NAFLD 30 , the relationship between histone acetylation and DNA mutations at known HCC-driver genes has not been reported. Our focus on non-cancerous, pre-mutational hepatocytes provides insight into the priming steps of an increasingly common cancer which has a five-year survival of 19% 31 and is responsible for more than 700,000 attributable deaths per year worldwide 32 , and may explain why HCC risk increases in NAFLD patients from the early stages of steatosis. It is also to our knowledge, the first evidence for abnormal histone acetylation being the initiating epigenetic event in carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease

Assante

Chandrasekaran

et al. 2021

Preprint

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The rate of nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing worldwide, but the steps in precancerous hepatocytes which lead to HCC driver mutations are not well understood. Here we provide evidence that metabolically-driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage to initiate carcinogenesis. Genome-wide histone acetylation is increased in steatotic livers of rodents fed high fructose or high fat diet. In vitro, steatosis relaxes chromatin and increases DNA damage marker γH2AX, which is reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and γH2AX are enriched at gene clusters in telomere-proximal regions which contain HCC tumor suppressors in hepatocytes and human fatty livers. Regions of metabolically-driven epigenetic change also have increased levels of DNA mutation in non-cancerous tissue from NAFLD patients. Finally, genome-scale network modelling indicates that redox balance is a key contributor to this mechanism. Thus abnormal histone hyperacetylation is a potential initiating event in HCC carcinogenesis.

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Epidemiology of non-alcoholic fatty liver disease and risk of hepatocellular carcinoma progression

Cited by 23 publications

References 55 publications

Cholesterol Metabolism: A Double-Edged Sword in Hepatocellular Carcinoma

Cholesterol Metabolism: A Double-Edged Sword in Hepatocellular Carcinoma

Apigenin attenuates atherosclerosis and non-alcoholic fatty liver disease through inhibition of NLRP3 inflammasome in mice

Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease

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