Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model

Yang, Tianwei; Poenisch, Marion; Khanal, Rajendra; Hu, Qing; Dai, Zhen; Li, Ruomeng; Song, Guangqi; Yuan, Qing; Yao, Qunyan; Shen, Xin; Taubert, Richard; Engel, Bastian; Jaeckel, Elmar; Vogel, Arndt; Falk, Christine S.; Schambach, Axel; Gerovska, Daniela; Araúzo‐Bravo, Marcos J.; Vondran, Florian W. R.; Cantz, Tobias; Horscroft, Nigel; Balakrishnan, Asha; Chevessier, Frédéric; Ott, Michael; Sharma, Amar Deep

doi:10.1016/j.jhep.2021.08.011

Cited by 103 publications

(95 citation statements)

References 33 publications

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“…The expression of HNF4a is markedly reduced in NAFLD patients and mouse models of NASH [2,3] or fibrotic livers. [4][5][6] Dysregulation of HNF4a expression is associated with many human diseases, such as NAFLD, liver cirrhosis, HCC, ulcerative colitis, colon cancer, and maturity onset diabetes of the young. In this review, we briefly overview the pathogenic mechanisms, diagnosis, and treatment of NAFLD, but focus on the regulation of hepatic HNF4a expression, the role of HNF4a in the pathogenesis of NAFLD, and the potential of HNF4a as a therapeutic target for NAFLD.…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte nuclear factor 4α in the pathogenesis of non-alcoholic fatty liver disease

Pan

Zhang

2022

Chinese Medical Journal

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Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common chronic liver disease worldwide. It refers to a range of liver conditions affecting people who drink little or no alcohol. NAFLD comprises non-alcoholic fatty liver and non-alcoholic steatohepatitis (NASH), the more aggressive form of NAFLD. NASH is featured by steatosis, lobular inflammation, hepatocyte injury, and various degrees of fibrosis. Although much progress has been made over the past decades, the pathogenic mechanism of NAFLD remains to be fully elucidated. Hepatocyte nuclear factor 4α (HNF4α) is a nuclear hormone receptor that is highly expressed in hepatocytes. Hepatic HNF4α expression is markedly reduced in NAFLD patients and mouse models of NASH. HNF4α has been shown to regulate bile acid, lipid, glucose, and drug metabolism. In this review, we summarize the recent advances in the understanding of the pathogenesis of NAFLD with a focus on the regulation of HNF4α and the role of hepatic HNF4α in NAFLD. Several lines of evidence have shown that hepatic HNF4α plays a key role in the initiation and progression of NAFLD. Recent data suggest that hepatic HNF4α may be a promising target for treatment of NAFLD.

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Section: Introductionmentioning

confidence: 99%

Hepatocyte nuclear factor 4α in the pathogenesis of non-alcoholic fatty liver disease

Pan

Zhang

2022

Chinese Medical Journal

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“…A different strategy to fight fibrosis is based on the gene delivery of human hepatocyte nuclear factor 4 alpha (HNF4A) via AAV vectors or mRNA containing LNP. This type of gene therapy was able to decrease the expression of genes involved in profibrogenic activity and revert fibrosis in several mouse models with induced or genetic cholestasis [ 100 ].…”

Section: Gene Therapymentioning

confidence: 99%

“…In this sense, an AAV8 vector expressing ACE2 was able to reduce liver fibrosis in early- and late-stage FVB Abcb4 -/- mice [ 117 ]. Moreover, hepatocyte-targeted administration of HNF4A mRNA encapsulated with a biodegradable lipid restored the metabolic activity of hepatocytes in FVB Abcb4 -/- mice, leading to a robust inhibition of fibrogenesis [ 100 ].…”

Section: Gene Therapymentioning

confidence: 99%

Gene Therapy for Acquired and Genetic Cholestasis

Martínez-García

Molina

González‐Aseguinolaza

et al. 2022

Biomedicines

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Cholestatic diseases can be caused by the dysfunction of transporters involved in hepatobiliary circulation. Although pharmacological treatments constitute the current standard of care for these diseases, none are curative, with liver transplantation being the only long-term solution for severe cholestasis, albeit with many disadvantages. Liver-directed gene therapy has shown promising results in clinical trials for genetic diseases, and it could constitute a potential new therapeutic approach for cholestatic diseases. Many preclinical gene therapy studies have shown positive results in animal models of both acquired and genetic cholestasis. The delivery of genes that reduce apoptosis or fibrosis or improve bile flow has shown therapeutic effects in rodents in which cholestasis was induced by drugs or bile duct ligation. Most studies targeting inherited cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), have focused on supplementing a correct version of a mutated gene to the liver using viral or non-viral vectors in order to achieve expression of the therapeutic protein. These strategies have generated promising results in treating PFIC3 in mouse models of the disease. However, important challenges remain in translating this therapy to the clinic, as well as in developing gene therapy strategies for other types of acquired and genetic cholestasis.

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“…Downregulation of HNF4α in obese mice and NASH patients [ 28 , 30 ] has been linked to NASH pathogenesis, supported by observations of alleviated fibrosis in CCl 4 -induced NASH models upon induced HNF4α overexpression [ 31 , 32 , 33 ]. Intriguingly, the occupancy of HNF4α at regulatory regions is redistributed in DIO [ 28 ], where the underlying mechanism may be linked to cooperation with C/EBPα [ 34 ].…”

Section: Identification Of Cis-regulatory Regions In the Diseased Livermentioning

confidence: 99%

Cell-Type Resolved Insights into the Cis-Regulatory Genome of NAFLD

Dam

Toft

Grøntved

2022

Cells

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The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly, and unmet treatment can result in the development of hepatitis, fibrosis, and liver failure. There are difficulties involved in diagnosing NAFLD early and for this reason there are challenges involved in its treatment. Furthermore, no drugs are currently approved to alleviate complications, a fact which highlights the need for further insight into disease mechanisms. NAFLD pathogenesis is associated with complex cellular changes, including hepatocyte steatosis, immune cell infiltration, endothelial dysfunction, hepatic stellate cell activation, and epithelial ductular reaction. Many of these cellular changes are controlled by dramatic changes in gene expression orchestrated by the cis-regulatory genome and associated transcription factors. Thus, to understand disease mechanisms, we need extensive insights into the gene regulatory mechanisms associated with tissue remodeling. Mapping cis-regulatory regions genome-wide is a step towards this objective and several current and emerging technologies allow detection of accessible chromatin and specific histone modifications in enriched cell populations of the liver, as well as in single cells. Here, we discuss recent insights into the cis-regulatory genome in NAFLD both at the organ-level and in specific cell populations of the liver. Moreover, we highlight emerging technologies that enable single-cell resolved analysis of the cis-regulatory genome of the liver.

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Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model

Cited by 103 publications

References 33 publications

Hepatocyte nuclear factor 4α in the pathogenesis of non-alcoholic fatty liver disease

Hepatocyte nuclear factor 4α in the pathogenesis of non-alcoholic fatty liver disease

Gene Therapy for Acquired and Genetic Cholestasis

Cell-Type Resolved Insights into the Cis-Regulatory Genome of NAFLD

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