Hepatocyte Nuclear Factor 4α Prevents the Steatosis‐to‐NASH Progression by Regulating p53 and Bile Acid Signaling (in mice)

Xu, Yanyong; Zhu, Yingdong; Hu, Shuwei; Xu, Yang; Stroup, Diane; Pan, Xiaoli; Bawa, Fathima Cassim; Chen, Shaoru; Gopoju, Raja; Yin, Liya; Zhang, Yanqiao

doi:10.1002/hep.31604

Cited by 54 publications

(44 citation statements)

References 43 publications

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“…In mouse models of high-fat diet (HFD) and high-fat high-cholesterol (HFCF) diet, increasing HNF4α expression protected against NASH by reducing expression of genes involved in inflammation, fibrogenesis and senescence (e.g., TNFα, IL6, IL1b, MCP1, F4/80 and p53), liver injury and ROS production. Deletion of p53 in hepatocytes with HNF4α overexpression (AAV8-ALB-hHNF4α) diminished the protective effect, suggesting that HNF4α exerted its effect through p53 [ 76 ]. Another study explored the potential global role of p53 in the complex network of pathways and cell–cell interactions involved in mediating injury and local inflammation in chronic liver disease and NAFLD [ 77 ].…”

Section: The Role Of Cellular Senescence In Fatty Liver Diseasementioning

confidence: 99%

The Potential Role of Cellular Senescence in Non-Alcoholic Fatty Liver Disease

Engelmann

Tacke

2022

IJMS

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Non-alcoholic fatty liver disease (NAFLD) represents an increasing global health burden. Cellular senescence develops in response to cellular injury, leading not only to cell cycle arrest but also to alterations of the cellular phenotype and metabolic functions. In this review, we critically discuss the currently existing evidence for the involvement of cellular senescence in NAFLD in order to identify areas requiring further exploration. Hepatocyte senescence can be a central pathomechanism as it may foster intracellular fat accumulation, fibrosis and inflammation, also due to secretion of senescence-associated inflammatory mediators. However, in some non-parenchymal liver cell types, such as hepatic stellate cells, senescence may be beneficial by reducing the extracellular matrix deposition and thereby reducing fibrosis. Deciphering the detailed interaction between NAFLD and cellular senescence will be essential to discover novel therapeutic targets halting disease progression.

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Section: The Role Of Cellular Senescence In Fatty Liver Diseasementioning

confidence: 99%

The Potential Role of Cellular Senescence in Non-Alcoholic Fatty Liver Disease

Engelmann

Tacke

2022

IJMS

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“…This is consistent with previous observations of SOCS3 as a direct target of STAT3 and the co-activation of STAT3 and SOCS3 in a human liver organoid model of fibrosis(72). We noticed that several genes in Figure 5F are direct targets of p53, which plays an essential role in driving apoptosis in NASH(47, 73, 74). Our analysis revealed that CDKN1A (p21) is uniquely associated with the STAT3 cistrome ( Figure 5F, G ), whereas other p53 targets (e.g., THBS1 , AEN , and GADD45B ) are associated with multiple TF cistromes ( Figure 5F, H ).…”

Section: Resultsmentioning

confidence: 95%

“…Differential transcription analysis identified 879 and 651 genes that are more transcriptionally active in NP and NR, respectively ( Figure 1E ; p < 0.05, padj < 0.2, normalized counts > 100, log2FC < or > 0 by DESeq2). The genes that are more transcriptionally active in NP than NR (hereafter, referred to as NP-activated genes) are enriched in pathways involved in neutrophil activation, immunity, and cytokine responses ( Figure 1F ), such as IL1B (37), IL6 (38), CCL2 (encoding MCP-1)(39, 40), CCL20 ( 16 ), HIF1A (41), TREM1 (42), PKM (43), CXCR2 (44), CRP (45, 46) , IL32 (47), and CD44 (48) ( Figure 1H ). The genes that are more transcriptionally active in NR than NP (hereafter, referred to as NR-activated genes) are enriched in pathways involved in fatty acid metabolism ( CPT2, ACADL, AIG1, ACAA2, ACSM5, ACOX2, BDH2, HAO2 ) and xenobiotic processes ( CYP2J2 )( 49 )( Figure 1G-H ).…”

Section: Resultsmentioning

confidence: 99%

Super-enhancer signature reveals key mechanisms associated with resistance to non-alcoholic steatohepatitis in humans with obesity

Hung

Sritharan

Vohl

et al. 2021

Preprint

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Non-alcoholic fatty liver disease (NAFLD), which often co-occurs with obesity and type 2 diabetes, is the most common cause of chronic liver disease worldwide. A subset of patients with NAFLD progress to the severe form known as non-alcoholic steatohepatitis (NASH), which increases the risk of developing hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. The molecular underpinnings of the progression from NAFLD to NASH in patients is poorly understood. Active enhancer landscapes are known to determine cell states and can point to key transcription factors (TF), genes, and pathways in disease pathogenesis or resistance. Also, while super-enhancers have helped reveal key disease drivers in several cancer types, they remain undefined in NASH. To define the enhancer signature of NASH-prone (NP) and NASH-resistant (NR) phenotypes in humans, we performed chromatin run-on sequencing (ChRO-seq) analysis on liver biopsies of individuals with severe obesity who were stratified into either the NP or NR group. We defined the active enhancer signature, super-enhancer linked genes, and the candidate TF networks in human NP and NR livers. Notably, we showed that NR-activated genes that are linked to NR-specific enhancers/super-enhancers are involved in serine and glycine biosynthesis (SHMT, BHMT) as well as glycine utilization (GLYAT, GATM). Overall, this study has defined for the first time the active enhancer/super-enhancer landscape and the underlying TF programs of NASH resistance in humans with obesity.

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“…Hence, it would be interesting to assess the metabolic effects of PFOA in PXR-knockout mice and in human hepatocytes with PXR silencing. (3) Reduction in HNF4α protein levels and activity [152,166], an effect which is expected to impair FAO and VLDL secretion [167].…”

Section: Perfluorooctanoic Acidmentioning

confidence: 99%

Xenobiotic-Induced Aggravation of Metabolic-Associated Fatty Liver Disease

Massart¹,

Begriche²,

Corlu³

et al. 2022

IJMS

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Metabolic-associated fatty liver disease (MAFLD), which is often linked to obesity, encompasses a large spectrum of hepatic lesions, including simple fatty liver, steatohepatitis, cirrhosis and hepatocellular carcinoma. Besides nutritional and genetic factors, different xenobiotics such as pharmaceuticals and environmental toxicants are suspected to aggravate MAFLD in obese individuals. More specifically, pre-existing fatty liver or steatohepatitis may worsen, or fatty liver may progress faster to steatohepatitis in treated patients, or exposed individuals. The mechanisms whereby xenobiotics can aggravate MAFLD are still poorly understood and are currently under deep investigations. Nevertheless, previous studies pointed to the role of different metabolic pathways and cellular events such as activation of de novo lipogenesis and mitochondrial dysfunction, mostly associated with reactive oxygen species overproduction. This review presents the available data gathered with some prototypic compounds with a focus on corticosteroids and rosiglitazone for pharmaceuticals as well as bisphenol A and perfluorooctanoic acid for endocrine disruptors. Although not typically considered as a xenobiotic, ethanol is also discussed because its abuse has dire consequences on obese liver.

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Hepatocyte Nuclear Factor 4α Prevents the Steatosis‐to‐NASH Progression by Regulating p53 and Bile Acid Signaling (in mice)

Cited by 54 publications

References 43 publications

The Potential Role of Cellular Senescence in Non-Alcoholic Fatty Liver Disease

The Potential Role of Cellular Senescence in Non-Alcoholic Fatty Liver Disease

Super-enhancer signature reveals key mechanisms associated with resistance to non-alcoholic steatohepatitis in humans with obesity

Xenobiotic-Induced Aggravation of Metabolic-Associated Fatty Liver Disease

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