Characterization of genetically engineered mouse hepatoma cells with inducible liver functions by overexpression of liver-enriched transcription factors

Yamamoto, Hiroki; Tonello, Jane Marie; Sambuichi, Takanori; Kawabe, Yoshinori; Ito, Akira; Kamihira, Masamichi

doi:10.1016/j.jbiosc.2017.07.011

Cited by 8 publications

(4 citation statements)

References 22 publications

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“…We have previously established a mouse hepatoma cell line with inducible enhanced liver functions, in which eight liver-enriched transcription factor (LETF) genes were transduced into murine hepatoma Hepa1-6 cells as the tetracycline-inducible expression units [ 25 , 26 , 27 ]. The genetically modified hepatoma cells maintained a hepatocyte phenotype through transcriptional regulation of liver-related genes by overexpression of LETF genes.…”

Section: Introductionmentioning

confidence: 99%

HepG2-Based Designer Cells with Heat-Inducible Enhanced Liver Functions

Kohno

Kawabe

Kamihira

2022

Cells

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Functional human hepatocytes have been a pivotal tool in pharmacological studies such as those investigating drug metabolism and hepatotoxicity. However, primary human hepatocytes are difficult to obtain in large quantities and may cause ethical problems, necessitating the development of a new cell source to replace human primary hepatocytes. We previously developed genetically modified murine hepatoma cell lines with inducible enhanced liver functions, in which eight liver-enriched transcription factor (LETF) genes were introduced into hepatoma cells as inducible transgene expression cassettes. Here, we establish a human hepatoma cell line with heat-inducible liver functions using HepG2 cells. The genetically modified hepatoma cells, designated HepG2/8F_HS, actively proliferated under normal culture conditions and, therefore, can be easily prepared in large quantities. When the expression of LETFs was induced by heat treatment at 43 °C for 30 min, cells ceased proliferation and demonstrated enhanced liver functions. Furthermore, three-dimensional spheroid cultures of HepG2/8F_HS cells showed a further increase in liver functions upon heat treatment. Comprehensive transcriptome analysis using DNA microarrays revealed that HepG2/8F_HS cells had enhanced overall expression of many liver function-related genes following heat treatment. HepG2/8F_HS cells could be useful as a new cell source for pharmacological studies and for constructing bioartificial liver systems.

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Section: Introductionmentioning

confidence: 99%

HepG2-Based Designer Cells with Heat-Inducible Enhanced Liver Functions

Kohno

Kawabe

Kamihira

2022

Cells

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“…Ct values of housekeeping and candidate genes were determined, and their expression was calculated by the DDCt method. Primer sequences for Rpl13a 47 , Apob 48 , Khk (isoform C) 49 , Gpat3 50 , Acly 16 , Fasn 16 , Scd1 16 and Mcp1 51 were from previous publications.…”

Section: Methodsmentioning

confidence: 99%

Determining the metabolic effects of dietary fat, sugars and fat-sugar interaction using nutritional geometry in a dietary challenge study with male mice

Facey

Dodgson

et al. 2023

Nat Commun

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The metabolic effects of sugars and fat lie at the heart of the “carbohydrate vs fat” debate on the global obesity epidemic. Here, we use nutritional geometry to systematically investigate the interaction between dietary fat and the major monosaccharides, fructose and glucose, and their impact on body composition and metabolic health. Male mice (n = 245) are maintained on one of 18 isocaloric diets for 18–19 weeks and their metabolic status is assessed through in vivo procedures and by in vitro assays involving harvested tissue samples. We find that in the setting of low and medium dietary fat content, a 50:50 mixture of fructose and glucose (similar to high-fructose corn syrup) is more obesogenic and metabolically adverse than when either monosaccharide is consumed alone. With increasing dietary fat content, the effects of dietary sugar composition on metabolic status become less pronounced. Moreover, higher fat intake is more harmful for glucose tolerance and insulin sensitivity irrespective of the sugar mix consumed. The type of fat consumed (soy oil vs lard) does not modify these outcomes. Our work shows that both dietary fat and sugars can lead to adverse metabolic outcomes, depending on the dietary context. This study shows how the principles of the two seemingly conflicting models of obesity (the “energy balance model” and the “carbohydrate insulin model”) can be valid, and it will help in progressing towards a unified model of obesity. The main limitations of this study include the use of male mice of a single strain, and not testing the metabolic effects of fructose intake via sugary drinks, which are strongly linked to human obesity.

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“…Studies have shown that most of the LETFs, including HNF1α, HNF1β, HNF3β (FOXA2), HNF4α, HNF6, C/EBP‐α, C/EBP‐β, and CREB‐H, are stably downregulated in a stage‐dependent manner during hepatocarcinogenesis, and forced re‐expression of LETFs can reprogram malignant cells to the functional hepatocytes, both in vitro and in vivo (Guzman‐Lepe & Cervantes‐Alvarez, 2018; Yamamoto et al, 2018; Y. Su et al, 2018) (Figure 7).…”

Section: Induction Of Hepatocyte Enriched Genes Can Drive Differentia...mentioning

confidence: 99%

Hepatogenesis and hepatocarcinogenesis: Alignment of the main signaling pathways

Shokouhian

Negahdari

et al. 2022

Journal Cellular Physiology

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Development is a symphony of cells differentiation in which different signaling pathways are orchestrated at specific times and periods to form mature and functional cells from undifferentiated cells. The similarity of the gene expression profile in malignant and undifferentiated cells is an interesting topic that has been proposed for many years and gave rise to the differentiation-therapy concept, which appears a rational insight and should be reconsidered. Hepatocellular carcinoma (HCC), as the sixth common cancer and the third leading cause of cancer death worldwide, is one of the health-threatening complications in communities where hepatotropic viruses are endemic. Sedentary lifestyle and high intake of calories are other risk factors. HCC is a complex condition in which various dimensions must be addressed, including heterogeneity of cells in the tumor mass, high invasiveness, and underlying diseases that limit the treatment options. Under these restrictions, recognizing, and targeting common signaling pathways during liver development and HCC could expedite to a rational therapeutic approach, reprograming malignant cells to well-differentiated ones in a functional state. Accordingly, in this review, we

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Characterization of genetically engineered mouse hepatoma cells with inducible liver functions by overexpression of liver-enriched transcription factors

Cited by 8 publications

References 22 publications

HepG2-Based Designer Cells with Heat-Inducible Enhanced Liver Functions

HepG2-Based Designer Cells with Heat-Inducible Enhanced Liver Functions

Determining the metabolic effects of dietary fat, sugars and fat-sugar interaction using nutritional geometry in a dietary challenge study with male mice

Hepatogenesis and hepatocarcinogenesis: Alignment of the main signaling pathways

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