Dietary fructose-induced hepatocellular carcinoma development manifested in mice lacking apoptosis inhibitor of macrophage (AIM).
The consumption of fructose, including the use of high-fructose corn syrup as a sweetener, has increased continuously in recent decades. Although the involvement of fructose in the development of metabolic diseases has been emphasized recently, whether fructose intake increases susceptibility to steatosis-associated hepatocellular carcinoma (HCC) is unclear. Here, we investigated this issue using mice lacking a circulating protein, apoptosis inhibitor of macrophage (AIM, encoded by cd5l). AIM does not induce carcinogenesis of hepatocytes, but provokes necrotic death specifically in AIM-bound cancer cells through complement cascade activation, thereby preventing HCC tumor development in wild-type mice. When subjected to a high-fructose diet (HFrD), AIM-deficient (AIM-/-) mice showed liver steatosis and subsequent liver inflammation as well as fibrosis, but at much milder levels compared with mice fed a high-fat diet. However, AIM-/-mice were markedly susceptible to HCC tumor development, whereas no wild-type mice developed the disease. Systemic metabolic states, including obesity and insulin resistance, were similar in both types of mice after HFrD challenge, indicating no influence of AIM on HFrD-induced metabolic changes. Our results suggest that dietary fructose increases the risk for liver carcinogenesis and that individuals with low blood AIM levels may be susceptible to HCC under chronic fructose intake.
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
Takayuki
T
Ozawa
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
Natsumi
N
Maehara
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
Toshihiro
T
Kai
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
Satoko
S
Arai
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, 113-0033, Japan.|Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo, 113-0033, Japan.
Toru
T
Miyazaki
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000097:blood / Q000235:genetics / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced*; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D005260:Female; D005632:Fructose / Q000008:administration & dosage / Q000009:adverse effects*; D066248:High Fructose Corn Syrup / Q000008:administration & dosage / Q000009:adverse effects*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011971:Receptors, Immunologic / Q000097:blood / Q000235:genetics / Q000502:physiology*; D051116:Receptors, Scavenger; D012307:Risk Factors
D051017:Apoptosis Regulatory Proteins; C117272:Cd5l protein, mouse; D066248:High Fructose Corn Syrup; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D005632:Fructose