Role of PPARα and HNF4α in Stress-Mediated Alterations in Lipid Homeostasis

Konstandi, Maria; Shah, Yatrik M.; Matsubara, Tsutomu; Gonzalez, Frank J.

doi:10.1371/journal.pone.0070675

Cited by 23 publications

(21 citation statements)

References 65 publications

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“…HNF4A is a master metabolic regulatory factor responsible for the activation of the hepatic gluconeogenesis (16) and has been implicated in diabetes, inflammation, and lipid metabolism (17)(18)(19)(20)(21). In this context, diabetes has been associated with PD in numerous epidemiological studies (22)(23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease

Santiago

Potashkin

2015

Proc. Natl. Acad. Sci. U.S.A.

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Environmental and genetic factors are likely to be involved in the pathogenesis of Parkinson's disease (PD), the second most prevalent neurodegenerative disease among the elderly. Networkbased metaanalysis of four independent microarray studies identified the hepatocyte nuclear factor 4 alpha (HNF4A), a transcription factor associated with gluconeogenesis and diabetes, as a central regulatory hub gene up-regulated in blood of PD patients. In parallel, the polypyrimidine tract binding protein 1 (PTBP1), involved in the stabilization and mRNA translation of insulin, was identified as the most down-regulated gene. Quantitative PCR assays revealed that HNF4A and PTBP1 mRNAs were upand down-regulated, respectively, in blood of 51 PD patients and 45 controls nested in the Diagnostic and Prognostic Biomarkers for Parkinson's Disease. These results were confirmed in blood of 50 PD patients compared with 46 healthy controls nested in the Harvard Biomarker Study. Relative abundance of HNF4A mRNA correlated with the Hoehn and Yahr stage at baseline, suggesting its clinical utility to monitor disease severity. Using both markers, PD patients were classified with 90% sensitivity and 80% specificity. Longitudinal performance analysis demonstrated that relative abundance of HNF4A and PTBP1 mRNAs significantly decreased and increased, respectively, in PD patients during the 3-y followup period. The inverse regulation of HNF4A and PTBP1 provides a molecular rationale for the altered insulin signaling observed in PD patients. The longitudinally dynamic biomarkers identified in this study may be useful for monitoring disease-modifying therapies for PD.Parkinson's disease | HNF4A | PTBP1 | network analysis | blood biomarkers S ubstantial efforts have been devoted to the development of diagnostic strategies for Parkinson's disease (PD). In particular, changes in mRNA from cellular whole blood can facilitate the identification of dysregulated processes and diagnostic biomarkers for PD (1, 2). Several molecular signatures in blood have been identified. For example, 22 unique genes were found differentially expressed in blood of PD patients compared with healthy controls (1). Likewise, specific splice variants in blood were associated with PD in samples obtained from two independent clinical trials (2, 3). In addition, altered expression of the vitamin D receptor (VDR) in blood and reduced plasma levels of 25-hydroxy vitamin D 3 have been associated with PD (1, 4). Furthermore, plasma levels of the epidermal growth factor have been associated with cognitive decline in PD (5).Environmental stressors and genetic factors are most likely involved in the pathogenesis of PD. Among the genetic factors associated with PD, mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common cause of autosomal dominant PD (6) and a considerable risk factor in idiopathic forms of the disease (7,8). Given the complex interaction between environmental and genetic factors in sporadic PD, we integrated four independent microarray s...

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Section: Discussionmentioning

confidence: 99%

Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease

Santiago

Potashkin

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, it was identified that hepatocyte nuclear factor-4α (HNF-4α) was a highly conserved member of the nuclear receptor superfamily, which was initially identified as a transcriptional factor required for liver-specific gene expression, and it was also critical in regulating the transcription of genes involved in glucose and lipid metabolism including APOA5 [20]. Intriguingly, previous study reported that HNF-4α and PPARα expression could be activated by hepatic protein kinase A (PKA) pathway [21]. More interestingly, it was reported that hepatic GPR30 combined with estrogen and in turn exerted its function by activating PKA pathway [18].…”

Section: Presentation Of the Hypothesismentioning

confidence: 99%

Estrogen lowers triglyceride via regulating hepatic APOA5 expression

et al. 2017

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Estrogen had been found to be negatively associated with serum triglyceride (TG) levels. Apolipoprotein A5 (APOA5), a novel member of apolipoprotein family, was reported to have a strong ability to decrease serum concentrations of TG. Clinical data found concentrations of APOA5 were higher in woman than that in men, and the negative relationship between APOA5 and TG levels was more significant in woman. These suggests APOA5 may involve in estrogen actions. Therefore, we hypothesize estrogen up-regulates serum concentrations of APOA5 and subsequently decreases serum TG levels. We will design the following experiments to test this hypothesis. (1) We will treat wild and APOA5-defeted ovariectomized hamster with or without estrogen to examine if estrogen could up-regulate concentrations of APOA5 and decrease TG levels. (2) We will treat HepG2 cells with estrogen and investigate the possible mechanisms.

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“…The present data indicate that stimulation of α 1 ‐ or β 1/2 ‐AR can efficiently reduce serum TRL levels via stimulation of TG hydrolysis, transport, metabolism and clearance, as well as inhibition of hepatic TG synthesis. Given that stress response includes adrenοceptor stimulation, our data further support that the stress‐induced changes in serum TG levels are mediated by α 1 ‐ and β 1/2 ‐ARs in a PPARα‐independent fashion, further supporting that PPARα activators, such as fibrates, may not be effective in the treatment of stress‐related hypertriglyceridemia. Additional research may identify these PPARα‐independent triggers providing alternative pharmacological targets for new pharmacological entities that may complement current therapies.…”

Section: Resultsmentioning

confidence: 52%

“…Despite these developments, the molecular triggers that are associated with the disease development and eventually with the elevated plasma, TRL accumulation remain largely unexplored. There is a strong evidence that both, central and peripheral nervous systems, may be involved in this regulation .…”

Section: Discussionmentioning

confidence: 99%

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Adrenoceptor‐related decrease in serum triglycerides is independent of PPARα activation

et al. 2019

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Adrenoceptor (AR)‐linked pathways belong to the major components of the stress response system and are associated with the pathophysiology of diseases within the spectrum of metabolic syndrome. In this study, the role of adrenoceptor stimulation in serum triglyceride (TG) regulation in mice was investigated. For this purpose, α1‐ARs were activated with phenylephrine (PH) and β1/2‐ARs with isoprenaline (ISOP). Both AR agonists markedly reduced serum TG levels independently of PPARα activation. These drugs also significantly activated the hormone‐sensitive lipase in the white adipose tissue indicating increased mobilization of TGs in this tissue. In addition, PH and ISOP up‐regulated Lpl, Nr4A, Dgat1, Mttp, Aadac and Cd36 genes, critical in TG regulation, whereas the observed decrease in serum TG levels was independent of the hepatic very low‐density lipoprotein (VLDL)‐TG secretion. Interestingly, PH and ISOP also inactivated the hepatic insulin/PI3k/AKT/FoxO1 signaling pathway, holding a critical role in the regulation of genes involved in TG synthesis. Taken together, the findings of the present study indicate that stimulation of α1‐ and β1/2‐ARs markedly reduced serum TG steady‐state levels as a result of alterations in TG synthesis, uptake, transport, hydrolysis, metabolism and clearance, an effect induced by PPARα independent mechanisms.

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Role of PPARα and HNF4α in Stress-Mediated Alterations in Lipid Homeostasis

Cited by 23 publications

References 65 publications

Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease

Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease

Estrogen lowers triglyceride via regulating hepatic APOA5 expression

Adrenoceptor‐related decrease in serum triglycerides is independent of PPARα activation

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