Liver X receptor α (LXRα/NR1H3) regulates differentiation of hepatocyte-like cells via reciprocal regulation of HNF4α

Chen, Kai-Ting; Pernelle, Kélig; Tsai, Yuan-Hau; Wu, Yu‐Hsuan; Hsieh, Jui-Yu; Liao, Ko-Hsun; Guguen‐Guillouzo, Christiane; Wang, Hsei‐Wei

doi:10.1016/j.jhep.2014.07.025

Cited by 19 publications

(13 citation statements)

References 53 publications

(54 reference statements)

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“…The overexpression of FXR after the intake of tomato juice in animals with steatosis may be beneficial in the prevention and treatment of NAFLD, since it plays crucial roles in the mediation of multiple genes associated with lipid and glucose metabolism and the inflammation response [ 50 ]. The HNF4A gene encodes the hepatocyte nuclear factor 4α, and it is known to modulate regulatory elements in the promoters and enhancers of genes involved in cholesterol, fatty acid, and glucose metabolism [ 53 , 54 ]. This gene was upregulated in HL rats, in comparison with both NA and HA rats.…”

Section: Discussionmentioning

confidence: 99%

Tomato Juice Supplementation Influences the Gene Expression Related to Steatosis in Rats

et al. 2018

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The objective of this work was to identify the effect of tomato juice on the expression of genes and levels of metabolites related to steatosis in rats. Male Sprague Dawley rats (8 weeks-old) were grouped (6 rats/group) in four experimental groups: NA (normal diet and water), NL (normal diet and tomato juice), HA (high-fat diet and water), and HL (high-fat diet and tomato juice). After an intervention period of 5 weeks, rats were sacrificed and biochemical parameters, biomarkers of oxidative stress, liver metabolites, and gene expression were determined. Although the H diet provoked dislipemia related to steatosis, no changes in isoprostanes or liver malondialdehyde (MDA) were observed. Changes in the gene expression of the HA group were produced by the high consumption of fat, whereas the consumption of tomato juice had different effects, depending on the diet. In the NL group, the genes involved in β-oxidation were upregulated, and in groups NL and HL upregulation of CD36 and downregulation of APOB and LPL were observed. In addition, in the HL group the accumulation of lycopene upregulated the genes FXR and HNF4A, which have been suggested as preventive factors in relation to steatosis. Regarding the metabolomics study, intake of tomato juice stimulated the biosynthesis of glutathione and amino acids of the transulfurization pathway, increasing the levels of metabolites related to the antioxidant response.

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Section: Discussionmentioning

confidence: 99%

Tomato Juice Supplementation Influences the Gene Expression Related to Steatosis in Rats

et al. 2018

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“…We infused a significantly lower amount of cells, 1 million, which corresponds to 1–1.5 % of the mouse hepatocyte mass, which was enough to rescue half of the animals. Interestingly, hepatocytes derived from the HepaRG cell line were able to rescue CCL4-treated animals only when the cells were transduced with LXRα [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Transplantation of hESC-derived hepatocytes protects mice from liver injury

et al. 2015

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BackgroundHepatic cell therapy has become a viable alternative to liver transplantation for life-threatening liver diseases. However, the supply of human hepatocytes is limited due to the shortage of suitable donor organs required to isolate high-quality cells. Human pluripotent stem cells reflect a potential renewable source for generating functional hepatocytes. However, most differentiation protocols use undefined matrices or factors of animal origin; as such, the resulting hepatocytes are not Good Manufacturing Practice compliant. Moreover, the preclinical studies employed to assess safety and function of human embryonic stem cell (hESC)-derived hepatocytes are generally limited to immunodeficient mice. In the present study, we evaluate the generation of hepatocytes under defined conditions using a European hESC line (VAL9) which was derived under animal-free conditions. The function capacity of VAL9-derived hepatocytes was assessed by transplantation into mice with acetaminophen-induced acute liver failure, a clinically relevant model.MethodsWe developed a protocol that successfully differentiates hESCs into bipotent hepatic progenitors under defined conditions, without the use of chromatin modifiers such as dimethyl sulphoxide. These progenitors can be cryopreserved and are able to generate both committed precursors of cholangiocytes and neonate-like hepatocytes.ResultsThirty days post-differentiation, hESCs expressed hepatocyte-specific markers such as asialoglycoprotein receptor and hepatic nuclear factors including HNF4α. The cells exhibited properties of mature hepatocytes such as urea secretion and UGT1A1 and cytochrome P450 activities. When transplanted into mice with acetaminophen-induced acute liver failure, a model of liver damage, the VAL9-derived hepatocytes efficiently engrafted and proliferated, repopulating up to 10 % of the liver. In these transplanted livers, we observed a significant decrease of liver transaminases and found no evidence of tumourigenicity. Thus, VAL9-derived hepatocytes were able to rescue hepatic function in acetaminophen-treated animals.ConclusionsOur study reveals an efficient protocol for differentiating VAL9 hESCs to neonatal hepatocytes which are then able to repopulate livers in vivo without tumour induction. The human hepatocytes are able to rescue liver function in mice with acetaminophen-induced acute toxicity. These results provide proof-of-concept that replacement therapies using hESC-derived hepatocytes are effective for treating liver diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0227-6) contains supplementary material, which is available to authorized users.

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“…We previously reported that the levels of albumin, CYP3A4, TTR, AFP, fibronectin and transthyretin were all regulated by HNF 4α [12]. Liver X receptor α (LXRα/NR1H3) accelerates hepatic differentiation in an HNF 4α-dependent manner, with hepatocyte-like cells exhibiting some functions of mature hepatocytes, including cytochrome P450 enzyme activity, secretion of urea and albumin, and an increase in glycogen storage [15].…”

Section: Hnf 4α Regulates Hepatic Differentiationmentioning

confidence: 99%

Role of Hepatocyte Nuclear Factor 4α in Regulating Hepatic Differentiation and the Inflammatory Response in HCC

Zhou¹,

Wang²,

Miao³

et al. 2019

Journal of Nutritional Oncology

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HNF4 is a nuclear hormone receptor protein mostly expressed in the liver but also expressed at lower levels in the gut, kidney, and pancreatic beta cells. Three different isoforms have been identified, HNF 4α, HNF 4β and HNF 4γ. The structure of HNF 4α protein has two transactivation Abstract: Limited treatment options are available for hepatocellular carcinoma (HCC), especially in the advanced stage, which is associated with a poor prognosis. Many studies have demonstrated that hepatocyte nuclear factor 4α (HNF 4α) plays an important role in hepatic differentiation and the carcinogenesis of HCC. HNF 4α critically regulates hepatic differentiation by controlling a large number of genes involved in hepatic functions including metabolism, xenobiotic detoxification, bile acid synthesis, and serum protein production. It has also been confirmed to play an important role in the inflammatory environment in HCC. Thus, HNF 4α is considered to be a promising target for the treatment of HCC. Some studies have demonstrated that regulating HNF 4α expression in HCC had beneficial effects in in vivo and in vitro experiments. We herein review the role of HNF 4α in regulating hepatic metabolism and the inflammatory response, aiming to provide some ideas on induced hepatic differentiation therapy and regulating the inflammatory microenvironment for the treatment of advanced HCC.

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Liver X receptor α (LXRα/NR1H3) regulates differentiation of hepatocyte-like cells via reciprocal regulation of HNF4α

Cited by 19 publications

References 53 publications

Tomato Juice Supplementation Influences the Gene Expression Related to Steatosis in Rats

Tomato Juice Supplementation Influences the Gene Expression Related to Steatosis in Rats

Transplantation of hESC-derived hepatocytes protects mice from liver injury

Role of Hepatocyte Nuclear Factor 4α in Regulating Hepatic Differentiation and the Inflammatory Response in HCC

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