Dietary fructose‐induced hepatocellular carcinoma development manifested in mice lacking apoptosis inhibitor of macrophage (<scp>AIM</scp>)

Ozawa, Takayuki; Maehara, Natsumi; Kai, Toshihiro; Arai, Satoko; Miyazaki, Toru

doi:10.1111/gtc.12446

Cited by 34 publications

(30 citation statements)

References 59 publications

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“…In addition, the present results could help to shed light on the recently evidenced cytotoxic effect of fructose and its metabolites in the induction of hepatocyte carcinogenesis [50]. …”

Section: Discussionmentioning

confidence: 90%

Fructose-Rich Diet Affects Mitochondrial DNA Damage and Repair in Rats

et al. 2017

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Evidence indicates that many forms of fructose-induced metabolic disturbance are associated with oxidative stress and mitochondrial dysfunction. Mitochondria are prominent targets of oxidative damage; however, it is not clear whether mitochondrial DNA (mtDNA) damage and/or its lack of repair are events involved in metabolic disease resulting from a fructose-rich diet. In the present study, we evaluated the degree of oxidative damage to liver mtDNA and its repair, in addition to the state of oxidative stress and antioxidant defense in the liver of rats fed a high-fructose diet. We used male rats feeding on a high-fructose or control diet for eight weeks. Our results showed an increase in mtDNA damage in the liver of rats fed a high-fructose diet and this damage, as evaluated by the expression of DNA polymerase γ, was not repaired; in addition, the mtDNA copy number was found to be significantly reduced. A reduction in the mtDNA copy number is indicative of impaired mitochondrial biogenesis, as is the finding of a reduction in the expression of genes involved in mitochondrial biogenesis. In conclusion, a fructose-rich diet leads to mitochondrial and mtDNA damage, which consequently may have a role in liver dysfunction and metabolic diseases.

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“…In addition, the present results could help to shed light on the recently evidenced cytotoxic effect of fructose and its metabolites in the induction of hepatocyte carcinogenesis [50]. …”

Section: Discussionmentioning

confidence: 90%

Fructose-Rich Diet Affects Mitochondrial DNA Damage and Repair in Rats

et al. 2017

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“…Indeed, most AIM −/− mice bear multiple HCC tumors when fed an HFD or a high-fructose diet for a year; in contrast, wild-type mice do not develop HCC tumors. 18,21 Overall, AIM prevents HCC tumor development through the elimination of cancerous hepatocytes. In addition, Lozano's group reported that AIM attaches to certain bacteria to induce coagulation, which aids effective bacterial eradication by the immune cells.…”

Section: Aim Influences Disease Progression In An Igm-free Mannermentioning

confidence: 99%

AIM associated with the IgM pentamer: attackers on stand-by at aircraft carrier

et al. 2018

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Circulating immunoglobulin M (IgM) exists in a pentameric form, possessing a polyreactive nature that responds not only to foreign antigens but also to autoantigens; thus, it is involved in both beneficial and detrimental immune responses, including protection from infection and the progression of autoimmunity. On the other hand, IgM also behaves as a carrier of the apoptosis inhibitor of macrophage (AIM) protein, storing a large amount of the inactivated form of AIM in the blood through this association. Under different disease conditions, AIM can dissociate from IgM locally or systemically to exert its function, inducing the removal of various biological debris such as excess fat, bacteria, cancer cells or dead cell debris. Most typically, upon induction of acute kidney injury (AKI), IgM-free AIM is filtered by the glomerulus in the kidney, which stimulates the clearance of intraluminal dead cells debris at the obstructed proximal tubules, thereby facilitating the repair of kidney injury. Interestingly, cats exhibit a deficiency in AIM release from IgM, which may increase their susceptibility to renal failure. Conversely, association with AIM inhibits IgM binding to the Fcα/μ receptor on follicular dendritic cells at the splenic germinal center, thereby protecting the IgM immune complex from Fcα/μ receptor-mediated internalization, which supports IgM-dependent antigen presentation to B cells and stimulates high-affinity IgG antibody production. The regulation of AIM-IgM binding, resulting from the discovery of reciprocal actions between AIM and IgM, could lead to the development of novel therapies against different diseases.

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“…CD5-like (CD5L) protein is a soluble glycoprotein, also known as apoptosis inhibitor of macrophage (AIM) (10). CD5L serves diverse roles in the relationship between lipid homeostasis and the immune response (11).…”

Section: Introductionmentioning

confidence: 99%

CD5L‑induced activation of autophagy is associated with hepatoprotection in ischemic reperfusion injury via the CD36/ATG7 axis

Lin

Zhuang

2020

Exp Ther Med

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Hepatic ischemia/reperfusion (I/R) injury is a side effect of major liver surgery that is difficult to prevent. I/R injury induces metabolic strain on hepatocytes and limits the tolerable ischemia during liver resection, as well as preservation times during transplantation. Additionally, I/R injury induces apoptosis in hepatocytes. CD5-like (CD5L), an inducer of autophagy, is a soluble scavenger cysteine-rich protein that modulates hepatocyte apoptosis. The aim of the present study was to determine if pharmacologic CD5L was protective against hepatic ischemia-reperfusion injury. Hepatocytes were subjected to I/R culture conditions, and apoptosis and caspase family activity were measured after I/R to model hepatic injury. Treatment with recombinant CD5L significantly suppressed apoptosis and caspase activity through modulating cellular autophagy to maintain activation of the cluster of differentiation 36 (CD36)-dependent autophagy-related 7 (ATG7) signaling pathway. The regulation loop between CD5L and the autophagy signaling pathway was identified to be associated with the inhibition of oxidative stress. Treatment with CD5L significantly inhibited cellular oxidative stress, which was confirmed by silencing the CD36 receptor or the autophagy related protein ATG7 using small interfering RNA, which reversed the antiapoptotic and antioxidative effects of CD5L on hepatocytes under I/R conditions. The results of the present study suggested that CD5L-mediated attenuation of hepatic I/R injury occurs through the CD36-dependent ATG7 pathway, accompanied by the inhibition of oxidative stress, which is associated with enhanced autophagy. In conclusion, the present study identifies CD5L as a novel therapeutic agent for hepatic I/R injury.

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Dietary fructose‐induced hepatocellular carcinoma development manifested in mice lacking apoptosis inhibitor of macrophage (AIM)

Cited by 34 publications

References 59 publications

Fructose-Rich Diet Affects Mitochondrial DNA Damage and Repair in Rats

Fructose-Rich Diet Affects Mitochondrial DNA Damage and Repair in Rats

AIM associated with the IgM pentamer: attackers on stand-by at aircraft carrier

CD5L‑induced activation of autophagy is associated with hepatoprotection in ischemic reperfusion injury via the CD36/ATG7 axis

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