A new preclinical model of western diet‐induced progression of non‐alcoholic steatohepatitis to hepatocellular carcinoma

Green, Christopher D.; Weigel, Cynthia; Brown, Ryan D.; Bédossa, Pierre; Dozmorov, Mikhail G.; Sanyal, Arun J.; Spiegel, Sarah

doi:10.1096/fj.202200346r

Cited by 24 publications

(23 citation statements)

References 64 publications

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“…In a newly developed preclinical NASH-HCC model with C57/BL6NJ mice, H19 is in the top ten upregulated genes (GSE197884) (Fig. 4c) [31]. We also found that H19 was significantly upregulated in the liver of HuR hKO mice fed with WDSW for 4 weeks (Fig.…”

Section: Hur Is a Suppressor Of Lncrna H19 Transcriptionmentioning

confidence: 54%

RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression

Wang

Tai

Way

et al. 2022

Preprint

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Background: NAFLD has become the most common chronic liver disease worldwide. Human antigen R (HuR), an RNA-binding protein, is an important post-transcriptional regulator. HuR has been reported as a key player in regulating lipid homeostasis in the liver and adipose tissues by using tissue-specific HuR knockout mice. However, the underlying mechanism by which hepatocyte-specific HuR regulates hepatic lipid metabolism under metabolic stress remains unclear and is the focus of this study.Methods: Hepatocyte-specific HuR deficient mice (HuR hKO ) and age-/gender-matched control mice, as well as long-noncoding RNA H19 knockout mice (H19 -/- ), were fed a Western Diet plus sugar water (WDSW). Hepatic lipid accumulation, inflammation and fibrosis were examined by histology, RNA transcriptome analysis, qRT-PCR, and Western blot analysis. Bile acid composition was measured using LC-MS/MS. Results: Hepatocyte-specific deletion of HuR not only significantly increased hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also markedly induced inflammation by increasing immune cell infiltration and neutrophil activation. In addition, hepatic deficiency of HuR disrupted bile acid homeostasis and enhanced liver fibrosis. Mechanistically, HuR is a repressor of H19 expression. Analysis of a recently published dataset (GSE143358) identified H19 as the top upregulated gene in liver-specific HuR knockout mice. Similarly, hepatocyte-specific deficiency of HuR dramatically induced the expression of H19 and down-regulated the expression of sphingosine kinase 2 (SphK2). WDSW-induced hepatic lipid accumulation was alleviated in H19 -/- mice. Furthermore, downregulation of H19 alleviated WDSW-induced NAFLD in HuR hKO mice.Conclusions: HuR not only functions as an RNA binding protein to modulate post-transcriptional gene expression but also regulates H19 promoter activity. Hepatic HuR is an important regulator of hepatic lipid metabolism via modulating H19 expression.

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Section: Hur Is a Suppressor Of Lncrna H19 Transcriptionmentioning

confidence: 54%

RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression

Wang

Tai

Way

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In a newly developed preclinical NASH–HCC model with C57/BL6NJ mice, H19 is in the top ten upregulated genes (GSE197884) (Fig. 4 c) [ 32 ]. We also found that H19 was significantly upregulated in the liver of HuR hKO mice fed with WDSW for 4 weeks (Fig.…”

Section: Resultsmentioning

confidence: 99%

RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression

et al. 2022

Self Cite

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Background NAFLD has become the most common chronic liver disease worldwide. Human antigen R (HuR), an RNA-binding protein, is an important post-transcriptional regulator. HuR has been reported as a key player in regulating lipid homeostasis in the liver and adipose tissues by using tissue-specific HuR knockout mice. However, the underlying mechanism by which hepatocyte-specific HuR regulates hepatic lipid metabolism under metabolic stress remains unclear and is the focus of this study. Methods Hepatocyte-specific HuR deficient mice (HuRhKO) and age-/gender-matched control mice, as well as long-noncoding RNA H19 knockout mice (H19−/−), were fed a Western Diet plus sugar water (WDSW). Hepatic lipid accumulation, inflammation and fibrosis were examined by histology, RNA transcriptome analysis, qRT–PCR, and Western blot analysis. Bile acid composition was measured using LC–MS/MS. Results Hepatocyte-specific deletion of HuR not only significantly increased hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also markedly induced inflammation by increasing immune cell infiltration and neutrophil activation under metabolic stress. In addition, hepatic deficiency of HuR disrupted bile acid homeostasis and enhanced liver fibrosis. Mechanistically, HuR is a repressor of H19 expression. Analysis of a recently published dataset (GSE143358) identified H19 as the top-upregulated gene in liver-specific HuR knockout mice. Similarly, hepatocyte-specific deficiency of HuR dramatically induced the expression of H19 and sphingosine-1 phosphate receptor 2 (S1PR2), but reduced the expression of sphingosine kinase 2 (SphK2). WDSW-induced hepatic lipid accumulation was alleviated in H19−/− mice. Furthermore, the downregulation of H19 alleviated WDSW-induced NAFLD in HuRhKO mice. Conclusions HuR not only functions as an RNA binding protein to modulate post-transcriptional gene expression but also regulates H19 promoter activity. Hepatic HuR is an important regulator of hepatic lipid metabolism via modulating H19 expression.

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“…However, most experimental mice strains fed this type of diet rarely progress to severe forms of NASH or develop HCC, unless there is a genetic predisposition (Takahashi et al, 2012;Nakagawa et al, 2014). Green et al (2022) found the addition of high glucose and fructose water to HFD promoted spontaneous induction of NASH driven HCC after 54 weeks. Similarly, diet high in saturated fat, cholesterol and sucrose promote weight gain, insulin resistance, liver injury and inflammation that is comparable to the human disease phenotype (Machado et al, 2015).…”

Section: Preclinical Models To Study Non-alcoholic Fatty Liver Diseas...mentioning

confidence: 99%

Immunometabolic factors contributing to obesity-linked hepatocellular carcinoma

Akl

Widenmaier

2023

Front. Cell Dev. Biol.

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Hepatocellular carcinoma (HCC) is a major public health concern that is promoted by obesity and associated liver complications. Onset and progression of HCC in obesity is a multifactorial process involving complex interactions between the metabolic and immune system, in which chronic liver damage resulting from metabolic and inflammatory insults trigger carcinogenesis-promoting gene mutations and tumor metabolism. Moreover, cell growth and proliferation of the cancerous cell, after initiation, requires interactions between various immunological and metabolic pathways that provide stress defense of the cancer cell as well as strategic cell death escape mechanisms. The heterogenic nature of HCC in addition to the various metabolic risk factors underlying HCC development have led researchers to focus on examining metabolic pathways that may contribute to HCC development. In obesity-linked HCC, oncogene-induced modifications and metabolic pathways have been identified to support anabolic demands of the growing HCC cells and combat the concomitant cell stress, coinciding with altered utilization of signaling pathways and metabolic fuels involved in glucose metabolism, macromolecule synthesis, stress defense, and redox homeostasis. In this review, we discuss metabolic insults that can underlie the transition from steatosis to steatohepatitis and from steatohepatitis to HCC as well as aberrantly regulated immunometabolic pathways that enable cancer cells to survive and proliferate in the tumor microenvironment. We also discuss therapeutic modalities targeted at HCC prevention and regression. A full understanding of HCC-associated immunometabolic changes in obesity may contribute to clinical treatments that effectively target cancer metabolism.

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A new preclinical model of western diet‐induced progression of non‐alcoholic steatohepatitis to hepatocellular carcinoma

Cited by 24 publications

References 64 publications

RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression

RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression

RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression

Immunometabolic factors contributing to obesity-linked hepatocellular carcinoma

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