Hepsin enhances liver metabolism and inhibits adipocyte browning in mice

Li, Shuo; Peng, Jianhao; Wang, Hao; Zhang, Wei; Brown, J. Mark; Zhou, Yiqing; Wu, Qingyu

doi:10.1073/pnas.1918445117

Cited by 29 publications

(50 citation statements)

References 55 publications

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“…The mice also had high food and water intakes, which is in an agreement with a high basal metabolic rate [78]. Further studies in hepsin KO mice identified an adipose browning phenotype, as indicated by low adipose weights, small adipocyte sizes, increased glucose uptakes, and high levels of brown adipocyte markers (Ucp1, uncoupling protein 1 and Cidea, cell death-inducing DFFA-like effector A) in both white and brown adipose tissues [78]. Brown adipocytes are mitochondria-rich, thermogenic, and metabolically active.…”

Section: Adipose Tissuessupporting

confidence: 75%

“…Latest studies indicate that the primary function of hepsin in the liver is to regulate glucose, lipid, and protein metabolism [78]. Hepsin KO mice have low levels of liver glycogen and triglyceride, blood glucose, and serum triglyceride, free fatty acids, and cholesterol.…”

Section: Livermentioning

confidence: 99%

“…The hepsin function in the liver is mediated likely by proteolytic conversion of prohepatocyte growth factor (pro-HGF) to HGF, a potent ligand for Met [78] (Fig. 2).…”

Section: Livermentioning

confidence: 99%

“…In hepsin KO mice, liver pro-HGF levels are increased, whereas serum HGF levels are decreased [76,78]. Reduced Met, Akt, Gsk3, and mTOR phosphorylation is also found in hepsin KO livers [76,78]. Intravenous injection of recombinant HGF increased Met, Akt, Gsk3, and mTOR phosphorylation in hepsin KO mouse livers [78].…”

Section: Livermentioning

confidence: 99%

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Hepsin: a multifunctional transmembrane serine protease in pathobiology

Wang

Sun

et al. 2020

The FEBS Journal

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Cell membrane-bound serine proteases are important in the maintenance of physiological homeostasis. Hepsin is a type II transmembrane serine protease highly expressed in the liver. Recent studies indicate that hepsin activates prohepatocyte growth factor in the liver to enhance Met signaling, thereby regulating glucose, lipid, and protein metabolism. In addition, hepsin functions in nonhepatic tissues, including the adipose tissue, kidney, and inner ear, to regulate adipocyte differentiation, urinary protein processing, and auditory function, respectively. In mouse models, hepsin deficiency lowers blood glucose, lipid, and protein levels, impairs uromodulin assembly in renal epithelial cells, and causes hearing loss. Elevated hepsin expression has also been found in many cancers. As a type II transmembrane protease, cell surface expression and zymogen activation are essential for hepsin activity. In this review, we discuss the current knowledge regarding hepsin biosynthesis, activation, and functions in pathobiology.

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Section: Adipose Tissuessupporting

confidence: 75%

Section: Livermentioning

confidence: 99%

“…The hepsin function in the liver is mediated likely by proteolytic conversion of prohepatocyte growth factor (pro-HGF) to HGF, a potent ligand for Met [78] (Fig. 2).…”

Section: Livermentioning

confidence: 99%

Section: Livermentioning

confidence: 99%

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Hepsin: a multifunctional transmembrane serine protease in pathobiology

Wang

Sun

et al. 2020

The FEBS Journal

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“…Moreover, the expression of MET, a specific receptor of HGF, can also be upregulated by hepsin. 14,42 Accumulating evidence has demonstrated that the miR-222 level is increased by MET. 20,21 Based on these data, we hypothesize that miR-222 can be modulated by hepsin.…”

Section: Discussionmentioning

confidence: 99%

<p>Hepsin Promotes Epithelial–Mesenchymal Transition and Cell Invasion Through the miR-222/PPP2R2A/AKT Axis in Prostate Cancer</p>

Li¹,

Li²,

Yang³

et al. 2020

OTT

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Purpose: To determine the role and underlying mechanism of hepsin in epithelial-mesenchymal transition (EMT) and cell invasion in prostate cancer. Methods: The expression of hepsin in prostate cancer tissue samples and cell lines was measured by immunohistochemical staining and Western blotting. The EMT and cell invasion abilities of prostate cancer cells were detected by Western blot and transwell assays. RNA transfection was used to inhibit or overexpress related genes. The expression of miR-222 was detected by RT-qPCR. A dual-luciferase reporter gene assay was performed to determine the target of miR-222. Results: Hepsin expression was upregulated in prostate cancer tissue samples and cell lines. Inhibition of hepsin attenuated EMT and cell invasion and downregulated the expression of miR-222. Decreased miR-222 expression enhanced the level of PPP2R2A, which in turn attenuated the AKT signaling. Activation of miR-222 or AKT could block the inhibitory effects on EMT and cell invasion induced by hepsin deficiency. Conclusion: Hepsin promotes EMT and cell invasion through the miR-222/PPP2R2A/AKT axis in prostate cancer.

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Hepsin as a potential therapeutic target for alleviating acetaminophen-induced hepatotoxicity via gap-junction regulation and oxidative stress modulation

Tsai,

Chen,

et al. 2024

Cell Biol Toxicol

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Acetaminophen (APAP) overdose is a leading cause of drug-induced liver damage, highlighting the limitations of current emergency treatments that primarily involve administering the glutathione precursor N-acetylcysteine and supportive therapy. This study highlights the essential protective role of the type II transmembrane serine protease (TTSP), hepsin, in mitigating acetaminophen-induced liver injury, particularly through its regulation of gap junction (GJ) abundance in response to reactive oxygen stress in the liver. We previously reported that reduced levels of activated hepatocyte growth factor and the c-Met receptor tyrosine kinase—both of which are vital for maintaining cellular redox balance—combined with increased expression of GJ proteins in hepsin-deficient mice. Here, we show that hepsin deficiency in mice exacerbates acetaminophen toxicity compared to wild-type mice, leading to more severe liver pathology, elevated oxidative stress, and greater mortality within 6 h after exposure. Administering hepsin had a protective effect in both mouse models, reducing hepatotoxicity by modulating GJ abundance. Additionally, transcriptome analysis and a functional GJ inhibitor have highlighted hepsin's mechanism for managing oxidative stress. Combining hepsin with relatively low doses of N-acetylcysteine had a synergistic effect that was more efficacious than high-dose N-acetylcysteine alone. Our results illustrate the crucial role of hepsin in modulating the abundance of hepatic GJs and reducing oxidative stress, thereby offering early protection against acetaminophen-induced hepatotoxicity and a new, combination approach. Emerging as a promising therapeutic target, hepsin holds potential for combination therapy with N-acetylcysteine, paving the way for novel approaches in managing drug-induced liver injury. Graphical Abstract 1. Hepsin−/− mice exhibit exacerbated APAP toxicity, resulting in more severe liver damage, elevated oxidative stress, and higher mortality. 2. Hepsin is crucial in protecting against APAP-induced liver injury by regulating gap junctions and reducing oxidative stress. 3. Combining hepsin with low doses of N-acetylcysteine provides greater protection against APAP-induced hepatotoxicity than high-dose NAC alone.

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Hepsin enhances liver metabolism and inhibits adipocyte browning in mice

Cited by 29 publications

References 55 publications

Hepsin: a multifunctional transmembrane serine protease in pathobiology

Hepsin: a multifunctional transmembrane serine protease in pathobiology

<p>Hepsin Promotes Epithelial–Mesenchymal Transition and Cell Invasion Through the miR-222/PPP2R2A/AKT Axis in Prostate Cancer</p>

Hepsin as a potential therapeutic target for alleviating acetaminophen-induced hepatotoxicity via gap-junction regulation and oxidative stress modulation

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