title: Obesity-associated mechanisms of hepatocarcinogenesis.
abstract: Obesity has been recognized as a key component of the metabolic syndrome, a cluster of risk factors associated with diabetes and cardiovascular morbidity. In addition, obesity has been linked to higher frequency of cancers in a variety of tissues including the liver. Liver cancer most often occurs as hepatocellular carcinoma (HCC) complicating cirrhosis due to chronic viral infection or toxic injury and remains the third leading cause of cancer death in the world. However, HCC is increasingly diagnosed among individuals with obesity and related disorders. As these metabolic conditions have become globally prevalent, they coexist with well-established risk factors of HCC and create a unique challenge for the liver as a chronically diseased organ. Obesity-associated HCC has recently been attributed to molecular mechanisms such as chronic inflammation due to adipose tissue remodeling and pro-inflammatory adipokine secretion, ectopic lipid accumulation and lipotoxicity, altered gut microbiota, and disrupted senescence in stellate cells, as well as insulin resistance leading to increased levels of insulin and insulin-like growth factors. These mechanisms synergize with those occurring in chronic liver disease resulting from other etiologies and accelerate the development of HCC before or after the onset of cirrhosis. Increasingly common interactions between oncogenic pathways linked to obesity and chronic liver disease may explain why HCC is one of the few malignancies with rising incidence in developed countries. Better understanding of this complex process will improve our strategies of cancer prevention, prediction, and surveillance.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY.
authors.forename: Raffi
authors.initials: R
authors.lastname: Karagozian
authors.affiliation: Liver Research Center, Rhode Island Hospital and Alpert School of Medicine, Brown University, Providence, Rhode Island.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Derdák
authors.affiliation: Department of Medicine, VA Boston Healthcare System and Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Electronic address: gbaffy@partners.org.
authors.forename: György
authors.initials: G
authors.lastname: Baffy
mesh_terms: D054392:Adipokines / Q000009:adverse effects / Q000378:metabolism; D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000209:etiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D006801:Humans; D018836:Inflammation Mediators / Q000009:adverse effects / Q000378:metabolism; D007328:Insulin / Q000502:physiology; D008113:Liver Neoplasms / Q000453:epidemiology / Q000209:etiology*; D009765:Obesity / Q000150:complications* / Q000453:epidemiology; D013002:Somatomedins / Q000502:physiology
chemical_list: D054392:Adipokines; D018836:Inflammation Mediators; D007328:Insulin; D013002:Somatomedins
keywords: Adipose tissue remodeling; Hepatocellular carcinoma; Insulin resistance; Lipotoxicity; Nonalcoholic fatty liver disease