From Liver Fat to Cancer: Perils of the Western Diet

Kim, Ju Youn; He, Feng; Karin, Michael

doi:10.3390/cancers13051095

Cited by 25 publications

(25 citation statements)

References 154 publications

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“…Other studies on AAV gene delivery to the liver have not detected NASH or HCC. This is expected because all murine models of NASH and HCC progression require a hypercaloric diet, presumably to induce an inflammatory environment (56, 57).…”

Section: Discussionmentioning

confidence: 99%

“…However, our new results show that high levels of FVIII gene expression by itself, even if transient and very likely independent of insertional events, can induce HCC in the context of a HFD. All murine models of NASH and HCC progression require a hypercaloric diet, presumably to induce an inflammatory environment (66, 67). HCC has not been observed in animals treated with AAV-FVIII vectors but these animals were not subjected a HFD challenge.…”

Section: Discussionmentioning

confidence: 99%

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Ectopic FVIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

Deng

Kapelanski-Lamoureux

Gao

et al. 2021

Preprint

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Clotting Factor VIII (FVIII) is the protein deficient in hemophilia A (HA), an X chromosome-linked bleeding disorder affecting 24.6 per 100,000 males at birth. Scientists and clinical physicians have been striving hard to find a cure for this disease. Presently, HA therapy involves prophylactic infusion of plasma-derived or recombinant-derived FVIII. Recent clinical studies have reported success using recent adeno-associated-virus (AAV) vector mediated delivery of a FVIII gene. FVIII is a 330 kDa glycoprotein comprised of three domains (A1-A2-B-A3-C1-C2). The B domain is dispensable and B domain-deleted (BDD) FVIII is used in the clinic as an effective protein replacement therapy for HA. Previously, we observed that hydrodynamic tail vein injection of the BDD-FVIII vector resulted in FVIII aggregation and endoplasmic reticulum (ER) stress in murine livers. Additionally, mice that were exposed to transient ER stress and then fed a high fat diet (HFD) for 9 months developed hepatocellular carcinoma (HCC). Therefore, we deduced that ectopic transient expression of FVIII in hepatocytes of mice with subsequent HFD feeding may also develop HCC. Here, we tested hepatocyte expression of two BDD-FVIII variants in vivo. BDD-FVIII aggregates in the ER and induces hepatocyte apoptosis, and N6-FVIII is more efficiently folded and secreted from the ER and causes less hepatocyte apoptosis. We performed tail vein injections of vectors directing expression of BDD-FVIII or N6-BDD to hepatocytes of 6-week old mice. One week after injection, mice were fed 60% HFD for 65 weeks. We found that 50% of mice that received N6-BDD developed liver tumors; in contrast, 90% of mice given BDD-FVIII developed liver tumors. Of the mice injected with BDD-FVIII, 30% developed carcinomas and 60% developed adenomas. Similar masses were not observed in mice that received empty vector. These findings raise concerns about the safety of long-term ectopic expression of FVIII in hepatocytes during FVIII gene therapy

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ectopic FVIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

Deng

Kapelanski-Lamoureux

Gao

et al. 2021

Preprint

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“…Among these conditions, simple steatosis of hepatocytes only rarely leads to clinical symptoms; it is also difficult to make a diagnosis, as the only effective method of determination so far is biopsy, which is invasive and thus generally not acceptable to patients who are suspected of having such a disease. However, fatty liver may be a precursor to all of the other, more severe states of liver disease, even cancer ( 54 , 55 ). Understanding the mechanisms underlying the etiology and pathology of fatty liver diseases therefore has definite clinical significance in prevention, early prognosis, and treatment.…”

Section: Fatty Liver and Non-alcoholic Fatty Liver Diseasementioning

confidence: 99%

“…Thirdly, endotoxemia resulted from increased gut permeability is also associated with NAFLD pathogenesis, indicating the effects of gut dysbiosis on immune system ( 55 ). Bacteria-derived endotoxins such as lipopolysaccharide (LPS) are closely related with intestinal immune function ( 73 ).…”

Section: Gut Microbial Dysbiosis and Nafld: The Gut-liver Axismentioning

confidence: 99%

Oral and Gut Microbial Dysbiosis and Non-alcoholic Fatty Liver Disease: The Central Role of Porphyromonas gingivalis

et al. 2022

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Gut microbiota play many important roles, such as the regulation of immunity and barrier function in the intestine, and are crucial for maintaining homeostasis in living organisms. The disruption in microbiota is called dysbiosis, which has been associated with various chronic inflammatory conditions, food allergies, colorectal cancer, etc. The gut microbiota is also affected by several other factors such as diet, antibiotics and other medications, or bacterial and viral infections. Moreover, there are some reports on the oral-gut-liver axis indicating that the disruption of oral microbiota affects the intestinal biota. Non-alcoholic fatty liver disease (NAFLD) is one of the systemic diseases caused due to the dysregulation of the oral-gut-liver axis. NAFLD is the most common liver disease reported in the developed countries. It includes liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Recently, accumulating evidence supports an association between NAFLD and dysbiosis of oral and gut microbiota. Periodontopathic bacteria, especially Porphyromonas gingivalis, have been correlated with the pathogenesis and development of NAFLD based on the clinical and basic research, and immunology. P. gingivalis was detected in the liver, and lipopolysaccharide from this bacteria has been shown to be involved in the progression of NAFLD, thereby indicating a direct role of P. gingivalis in NAFLD. Moreover, P. gingivalis induces dysbiosis of gut microbiota, which promotes the progression of NAFLD, through disrupting both metabolic and immunologic pathways. Here, we review the roles of microbial dysbiosis in NAFLD. Focusing on P. gingivalis, we evaluate and summarize the most recent advances in our understanding of the relationship between oral-gut microbiome symbiosis and the pathogenesis and progression of non-alcoholic fatty liver disease, as well as discuss novel strategies targeting both P. gingivalis and microbial dysbiosis.

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“…[38] It has been demonstrated that multiple parallel hits drive not only CLD pathogenesis, but also the development of HCC on the background of CLD. [39] Although environmental exposure is increasingly identified as a potential risk factor for CLD, [40] few studies have investigated the impact of environmental exposure on the risk of developing HCC. The purpose of this study is to begin to address this gap in our knowledge.…”

Section: The Enhancement Of Hcc By Vc Exposure Leads To a Unique Epit...mentioning

confidence: 99%

Western diet unmasks transient low-level vinyl chloride exposure-induced tumorigenesis; potential role of the (epi-)transcriptome

Liu

Bannister

et al. 2022

Preprint

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Background & Aims: Vinyl chloride (VC) monomer is a volatile organic compound commonly used in industry to produce polyvinyl chloride (PVC). At high exposure levels, VC causes liver cancer and toxicant-associated steatohepatitis. However, lower exposure levels (i.e., < regulatory exposure limits) that do not directly damage the liver, enhance injury caused by Western diet (WD). Although these lower exposure levels are considered 'safe,' it is unknown if the long-term impact of transient low-concentration VC enhances the risk of liver cancer development. Low-concentration VC is especially a concern given that fatty liver disease is in and of itself a risk factor for the development of liver cancer. Methods: C57Bl/6J mice were fed WD or control diet (CD) for 1 year. During the first 12 weeks of feeding only, mice were also exposed to VC via inhalation at sub-regulatory limit concentrations (<1 ppm) or air for 6 hours/day, 5 days/week. Results: Feeding WD for 1 year caused significant hepatic injury, including steatohepatitis and moderate fibrosis, which was exacerbated by VC. Additionally, VC increased the number of tumors which ranged from moderately to poorly differentiated hepatocellular carcinoma (HCC). Transcriptomic analysis demonstrated VC-induced changes in metabolic but also ribosomal processes. Epitranscriptomic analysis showed a VC-induced shift of the modification pattern that has been associated with metabolic disease, mitochondrial dysfunction, and cancer. Conclusions: These data indicate that VC sensitizes the liver to other stressors (e.g., WD), resulting in enhanced tumorigenesis. These data raise concerns about a potential interaction between VC exposure and WD. Furthermore, it also emphasizes that current safety restrictions may be insufficient to account for other factors that can influence hepatotoxicity.

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From Liver Fat to Cancer: Perils of the Western Diet

Cited by 25 publications

References 154 publications

Ectopic FVIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

Ectopic FVIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

Oral and Gut Microbial Dysbiosis and Non-alcoholic Fatty Liver Disease: The Central Role of Porphyromonas gingivalis

Western diet unmasks transient low-level vinyl chloride exposure-induced tumorigenesis; potential role of the (epi-)transcriptome

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