NAFLD, NASH and liver cancer

Michelotti, Gregory A.; Machado, Mariana Verdelho; Diehl, Anna Mae

doi:10.1038/nrgastro.2013.183

Cited by 880 publications

(734 citation statements)

References 144 publications

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“…7 Pro-inflammatory cytokines produced by immune cells that are implicated in steatohepatitis also play a critical role in promoting cancer invasion and metastasis. 8,9 Inflammation in the liver microenvironment also contributes to carcinogenesis. 10 Depending on the tissue environment, macrophages can become polarized into M1 (inflammatory) or M2 (alternatively activated) phenotype.…”

Section: Introductionmentioning

confidence: 99%

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

et al. 2016

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Obesity-related inflammation promotes cancer development. Tissue resident macrophages affect tumor progression and the tumor micro-environment favors polarization into alternatively activated macrophages (M2) that facilitate tumor invasiveness. Here, we dissected the role of western diet-induced NASH in inducing macrophage polarization in a carcinogen initiated model of hepatocellular carcinoma (HCC). Adult C57BL/6 male mice received diethyl nitrosamine (DEN) followed by 24 weeks of high fat-high cholesterol-high sugar diet (HF-HC-HSD). We assessed liver MRI and histology, serum ALT, AFP, liver triglycerides, and cytokines. Macrophage polarization was determined by IL-12/TNFa (M1) and CD163/ CD206 (M2) expression using flow cytometry. Role of hif-1a-induced IL-10 was dissected in hepatocyte specific hif-1aKO and hif-1adPA (over-expression) mice. The western diet-induced features of NASH and accelerated HCC development after carcinogen exposure. Liver fibrosis and serum AFP were significantly increased in DEN C HF-HC-HSD mice compared to controls. Western diet resulted in macrophage (F4/ 80 C CD11b C ) infiltration to liver and DEN C HF-HC-HSD mice showed preferential increase in M2 macrophages. Isolated hepatocytes from western diet fed mice showed significant upregulation of the hypoxia-inducible transcription factor, hif-1a, and livers from hif-1a over-expressing mice had increased proportion of M2 macrophages. Primary hepatocytes from wild-type mice treated with DEN and palmitic acid in vitro showed activation of hif-1a and induction of IL-10, a M2 polarizing cytokine. IL-10 neutralization in hepatocyte-derived culture supernatant prevented M2 macrophage polarization and silencing hif-1a in macrophages blocked their M2 polarization. Therefore, our data demonstrate that NASH accelerates HCC progression via upregulation of hif-1a mediated IL-10 polarizing M2 macrophages.

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Section: Introductionmentioning

confidence: 99%

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

et al. 2016

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“…Although the overall rate of NASH in the NAFLD population is unclear, certain studies propose that NASH may affect up to 5% of the general population. The disease further progresses towards liver cirrhosis and hepatocellular carcinoma, a complication which is increasingly observed also in the non-cirrhotic NAFLD population [2,3]. The high rate of hepatocellular carcinoma in NAFLD requires special attention.…”

Section: Introductionmentioning

confidence: 99%

Non-Alcoholic Fatty Liver Disease: Cause or Effect of Metabolic Syndrome

et al. 2016

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Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease throughout the world. Pathophysiological insights into this disease have recently illustrated that various factors such as insulin resistance, innate immunity, metabolic inflammation, and the microbiota are of relevance. NAFLD, metabolic syndrome (MS), and type 2 diabetes (T2D) share many pathophysiological aspects, and inflammatory processes in the adipose tissue, gut, and liver have evolved to be of exceptional importance. Most of NAFLD patients are obese and encounter a high risk of developing MS and T2D. NAFLD, however, is also highly common in subjects with MS and T2D. Furthermore, reflecting its nature of a multisystem disease, NAFLD is associated with a high prevalence and incidence of cardiovascular and chronic kidney disease. These facts require screening strategies for MS/T2D in NAFLD patients and vice versa. Thus, the question of cause or effect cannot be answered as MS and NAFLD share many pathomechanisms, and at the time of either diagnosis both frequently coexist. This is also reflected by a global prevalence rate of 25% for both NAFLD and MS. For this reason, it is crucial that physicians are aware of the ‘unholy liaison' between MS, T2D, and NAFLD.

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“…Nonalcoholic fatty liver disease is a spectrum of liver disease including simple steatosis, nonalcoholic steatohepatitis (NASH), advanced hepatic fibrosis, liver cirrhosis, and hepatocellular carcinoma [42]. Aberrant expression of various microRNAs has been reported in patients with NASH [26,43].…”

Section: Altered Microrna Levels In Nonalcoholic Fatty Liver Diseasementioning

confidence: 99%

MicroRNA Function in Human Diseases

et al. 2013

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MicroRNAs are emerging as a hot topic in research, and rightfully so. They show great promise as targets of treatment and as markers for common human diseases, such as cancer and metabolic diseases. In this review, we address some of the basic questions regarding microRNA function in human disease and the clinical significance of microRNAs. Specifically, microRNAs in epigenetics, cancer, and metabolic diseases are discussed, with examples taken from cholangiocarcinoma and nonalcoholic fatty liver disease.

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NAFLD, NASH and liver cancer

Cited by 880 publications

References 144 publications

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

Non-Alcoholic Fatty Liver Disease: Cause or Effect of Metabolic Syndrome

MicroRNA Function in Human Diseases

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