Dataset Information

Hepatocyte nuclear factor 4α induces a tendency of differentiation and activation of rat hepatic stellate cells.

ABSTRACT:

Aim

To investigate the effect of hepatocyte nuclear factor 4α (HNF4α) on the differentiation and transformation of hepatic stellate cells (HSCs).

Methods

By constructing the recombinant adenovirus vector expressing HNF4α and HNF4α shRNA vector, and manipulating HNF4α expression in HSC-T6 cells, we explored the influence of HNF4α and its induction capacity in the differentiation of rat HSCs into hepatocytes.

Results

With increased expression of HNF4α mediated by AdHNF4α, the relative expression of Nanog was downregulated in HSC-T6 cells (98.33 ± 12.33 vs 41.33 ± 5.67, P < 0.001). Consequently, the expression of G-P-6 and PEPCK was upregulated (G-P-6: 14.34 ± 3.33 vs 42.53 ± 5.87, P < 0.01; PEPCK: 10.10 ± 4.67 vs 56.56 ± 5.25, P < 0.001), the expression of AFP and ALB was positive, and the expression of Nanog, Type I collagen, α-SMA, and TIMP-1 was significantly decreased. HNF4α also downregulated vimentin expression and enhanced E-cadherin expression. The ultrastructure of HNF4α-induced cells had more mitochondria and ribosomes compared with the parental cells. After silencing HNF4α expression, EPCK, E-cadherin, AFP, and ALB were downregulated and α-SMA and vimentin were upregulated.

Conclusion

HNF4α can induce a tendency of differentiation of HSCs into hepatocyte-like cells. These findings may provide an effective way for the treatment of liver diseases.

SUBMITTER: Liu K

PROVIDER: S-EPMC4438019 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Publications

Hepatocyte nuclear factor 4α induces a tendency of differentiation and activation of rat hepatic stellate cells.

Liu Kai K Guo Ming-Gao MG Lou Xiao-Li XL Li Xiao-Ya XY Xu Yang Y Ji Wei-Dan WD Huang Xuan-Dong XD Yang Jia-He JH Duan Ji-Cheng JC

World journal of gastroenterology 20150501 19

<h4>Aim</h4>To investigate the effect of hepatocyte nuclear factor 4α (HNF4α) on the differentiation and transformation of hepatic stellate cells (HSCs).<h4>Methods</h4>By constructing the recombinant adenovirus vector expressing HNF4α and HNF4α shRNA vector, and manipulating HNF4α expression in HSC-T6 cells, we explored the influence of HNF4α and its induction capacity in the differentiation of rat HSCs into hepatocytes.<h4>Results</h4>With increased expression of HNF4α mediated by AdHNF4α, the ...[more]

PMID: 26019449

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Project description:Simple Summary Did you know that alcohol abuse among people living with HIV (PLWH) is twice as frequent as in the general population? This undoubtedly makes alcohol abuse in the context of HIV a severe public health issue, which is often attributed to several comorbidities including liver disease. In fact, 50% of mortality from HIV-related liver disease in the United States is attributed to alcohol. Previously, we showed that an alcohol metabolite, acetaldehyde, drives HIV accumulation in hepatocytes, which generates oxidative stress leading to hepatocyte death. When large vesicles (apoptotic bodies) from dead hepatocytes are internalized by hepatic stellate cells (HSC), it causes their profibrotic activation. In fact, our data revealed that upon internalization of HIV-containing hepatocyte apoptotic bodies, HSC generate reactive oxygen species (ROS), which induce fibrosis by activating JNK-ERK1/2 and JAK-STAT3 pathways. Therefore, a potential therapeutic regimen for reducing liver fibrosis among PLWH should include ROS-scavenging antioxidants. Abstract Recently, we found that both HIV and acetaldehyde, an alcohol metabolite, induce hepatocyte apoptosis, resulting in the release of large extracellular vesicles called apoptotic bodies (ABs). The engulfment of these hepatocyte ABs by hepatic stellate cells (HSC) leads to their profibrotic activation. This study aims to establish the mechanisms of HSC activation after engulfment of ABs from acetaldehyde and HIV-exposed hepatocytes (ABAGS+HIV). In vitro experiments were performed on Huh7.5-CYP (RLW) cells to generate hepatocyte ABs and LX2 cells were used as HSC. To generate ABs, RLW cells were pretreated for 24 h with acetaldehyde, then exposed overnight to HIV1ADA and to acetaldehyde for 96 h. Thereafter, ABs were isolated from cell suspension by a differential centrifugation method and incubated with LX2 cells (3:1 ratio) for profibrotic genes and protein analyses. We found that HSC internalized ABs via the tyrosine kinase receptor, Axl. While the HIV gag RNA/HIV proteins accumulated in ABs elicited no productive infection in LX2 and immune cells, they triggered ROS and IL6 generation, which, in turn, activated profibrotic genes via the JNK-ERK1/2 and JAK-STAT3 pathways. Similarly, ongoing profibrotic activation was observed in immunodeficient NSG mice fed ethanol and injected with HIV-derived RLW ABs. We conclude that HSC activation by hepatocyte ABAGS+HIV engulfment is mediated by ROS-dependent JNK-ERK1/2 and IL6 triggering of JAK-STAT3 pathways. This can partially explain the mechanisms of liver fibrosis development frequently observed among alcohol abusing PLWH.

Dataset Information

Hepatocyte nuclear factor 4α induces a tendency of differentiation and activation of rat hepatic stellate cells.

Aim

Methods

Results

Conclusion

Publications

Hepatocyte nuclear factor 4α induces a tendency of differentiation and activation of rat hepatic stellate cells.

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