Paired related homeobox protein 1 regulates PDGF-induced chemotaxis of hepatic stellate cells in liver fibrosis

Gong, Jin; Han, Jian; He, Jianzhong; Liu, Jingmei; Han, Ping; Wang, Yunwu; Li, Mengke; Li, Dongxiao; Ding, Xiangming; Du, Zhipeng; Liao, Jiazhi; Tian, Dean

doi:10.1038/labinvest.2017.65

Cited by 23 publications

(16 citation statements)

References 42 publications

(48 reference statements)

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“…One of few established target genes of PRRX1 is tenascin C (TNC) 35,36 , a pro-fibrotic factor involved in a Twist1-Prrx1-TNC positive feedback loop in fibroblast activation 37 . Recent studies have revealed pro-fibrotic effects of PRRX1 in hepatic stellate cells 38 and lung fibroblasts 39 . In hepatic stellate cells, PRRX1 was shown to transactivate the COL1A1 promoter 40 .…”

Section: Discussionmentioning

confidence: 99%

COL6A3 expression in adipose tissue cells is associated with levels of the homeobox transcription factor PRRX1

Dankel

Grytten

Bjune

et al. 2020

Sci Rep

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Fibrillar collagen COL6α3 in adipose tissue has been associated with obesity, inflammation, insulin resistance and cancer. We here aimed to identify novel transcriptional regulators of COL6A3 expression. Based on a transcriptome dataset of adipose tissue, we identified strong correlations for 56 genes with COL6A3 mRNA, including targets of TGF-β/SMAD signaling. Among the identified candidates, the homeobox transcription factor PRRX1 showed a particularly striking co-expression with COL6A3, validated across several different cohorts, including patients with extreme obesity, insulin sensitive and resistant obesity (subcutaneous and omental), after profound fat loss (subcutaneous), and lean controls (subcutaneous). In human and mouse adipose cells, PRRX1 knockdown reduced COL6A3 mRNA and PRRX1 overexpression transactivated a reporter construct with the endogenous human COL6A3 promoter. Stable PRRX1 overexpression in 3T3-L1 cells induced Col6a3 mRNA threefold specifically after adipogenic induction, whereas TGF-β1 treatment upregulated Col6a3 mRNA also in the preadipocyte state. Interestingly, pro-inflammatory stimulus (i.e., TNF-α treatment) decreased PRRX1-mediated Col6a3 transactivation and mRNA expression, supporting a role for this mechanism in the regulation of adipose tissue inflammation. In conclusion, we identified the homeobox factor PRRX1 as a novel transcriptional regulator associated with COL6A3 expression, providing new insight into the regulatory mechanisms of altered adipose tissue function in obesity and insulin resistance.

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Section: Discussionmentioning

confidence: 99%

COL6A3 expression in adipose tissue cells is associated with levels of the homeobox transcription factor PRRX1

Dankel

Grytten

Bjune

et al. 2020

Sci Rep

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“…ETS1 is a known transducer of growth factor and ERK signaling controlling genes involved in inflammation, proliferation, and ECM remodeling 24,52–55 and has previously been detected in HSCs 55,56 . ETS1 is permissive of TGFβ signaling to Smad2/3-regulated genes in HaCaT keratinocytes, where 56% of Smad2/3-binding regions also contain ETS1 motifs 57 .…”

Section: Discussionmentioning

confidence: 99%

Transcriptional regulation of Hepatic Stellate Cell activation in NASH

Marcher

Bendixen

Terkelsen

et al. 2019

Sci Rep

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Non-alcoholic steatohepatitis (NASH) signified by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis is a growing cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. Hepatic fibrosis resulting from accumulation of extracellular matrix proteins secreted by hepatic myofibroblasts plays an important role in disease progression. Activated hepatic stellate cells (HSCs) have been identified as the primary source of myofibroblasts in animal models of hepatotoxic liver injury; however, so far HSC activation and plasticity have not been thoroughly investigated in the context of NASH-related fibrogenesis. Here we have determined the time-resolved changes in the HSC transcriptome during development of Western diet- and fructose-induced NASH in mice, a NASH model recapitulating human disease. Intriguingly, HSC transcriptional dynamics are highly similar across disease models pointing to HSC activation as a point of convergence in the development of fibrotic liver disease. Bioinformatic interrogation of the promoter sequences of activated genes combined with loss-of-function experiments indicates that the transcriptional regulators ETS1 and RUNX1 act as drivers of NASH-associated HSC plasticity. Taken together, our results implicate HSC activation and transcriptional plasticity as key aspects of NASH pathophysiology.

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“…It is known that ERK1/2 activation increases the expression of MMP9, a metalloprotease involved in degradation of the extracellular matrix (Duarte et al, 2015; Hamada et al, 2008) whose promoter contains AP1 binding domains (Loesch et al, 2010). Several studies have reported elevations of this metalloprotease during the fibrotic process in livers from both humans and rodents (Arthur, 2000), suggesting a pivotal role of ERK1/2 in its induction in HSCs (Gong et al, 2017; Loesch et al, 2010). Analysis of MMP9 expression revealed a significant increase in LX2 cells treated with IGF1; an effect that was abolished by the presence of PD98059 or in IRS2 -silenced cells in which ERK1/2 phosphorylation was decreased.…”

Section: Discussionmentioning

confidence: 99%

Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury

Villar-Lorenzo

Rada

Rey

et al. 2019

Disease Models &Amp; Mechanisms

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Insulin receptor substrate 2 (IRS2) is a key downstream mediator of insulin and insulin-like growth factor 1 (IGF1) signalling pathways and plays a major role in liver metabolism. The aim of this study was to investigate whether IRS2 had an impact on the hepatic fibrotic process associated with cholestatic injury. Bile duct ligation (BDL) was performed in wild-type (WT) and Irs2 -deficient (IRS2KO) female mice. Histological and biochemical analyses, together with fibrogenic and inflammatory responses were evaluated in livers from mice at 3, 7 and 28 days following BDL. We also explored whether activation of human hepatic stellate cells (HSCs) induced by IGF1 was modulated by IRS2. IRS2KO mice displayed reduced disruption of liver histology, such hepatocyte damage and excess deposition of extracellular matrix components, compared with WT mice at 3 and 7 days post-BDL. However, no histological differences between genotypes were found at 28 days post-BDL. The less pro-inflammatory profile of bile acids accumulated in the gallbladder of IRS2KO mice after BDL corresponded with the reduced expression of pro-inflammatory markers in these mice. Stable silencing of IRS2 or inhibition of ERK1/2 reduced the activation of human LX2 cells and also reduced induction of MMP9 upon IGF1 stimulation. Furthermore, hepatic MMP9 expression was strongly induced after BDL in WT mice, but only a slight increase was found in mice lacking IRS2. Our results have unravelled the signalling pathway mediated by IGF1R–IRS2–ERK1/2–MMP9 as a key axis in regulating HSC activation, which might be therapeutically relevant for targeting liver fibrosis.

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Paired related homeobox protein 1 regulates PDGF-induced chemotaxis of hepatic stellate cells in liver fibrosis

Cited by 23 publications

References 42 publications

COL6A3 expression in adipose tissue cells is associated with levels of the homeobox transcription factor PRRX1

COL6A3 expression in adipose tissue cells is associated with levels of the homeobox transcription factor PRRX1

Transcriptional regulation of Hepatic Stellate Cell activation in NASH

Insulin receptor substrate 2 (IRS2) deficiency delays liver fibrosis associated with cholestatic injury

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