LSEC Fenestrae Are Preserved Despite Pro-inflammatory Phenotype of Liver Sinusoidal Endothelial Cells in Mice on High Fat Diet

Kuś, Edyta; Kaczara, Patrycja; Czyżyńska-Cichoń, Izabela; Szafranska, Karolina; Zapotoczny, Bartłomiej; Kij, Agnieszka; Sowińska, Agnieszka; Kotlinowski, Jerzy; Mateuszuk, Łukasz; Czarnowska, E.; Szymoński, Marek; Chłopicki, Stefan

doi:10.3389/fphys.2019.00006

Cited by 40 publications

(47 citation statements)

References 60 publications

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“…Capillarisation is analogous with endothelial dysfunction, in which LSEC can no longer maintain HSC quiescence in response to shear stress signals ( Deleve et al, 2008 ; Xie et al, 2012 ), and together these processes precede fibrosis ( Horn et al, 1987 ; Fraser et al, 1991 ; Pasarín et al, 2012 ; Baiocchini et al, 2019 ). A recent study, however, showed that LSEC dysfunction and loss of fenestrations following chronic metabolic stress do not always go hand in hand ( Kus et al, 2019 ). Specifically, it was shown that mice subject to high-fat diet developed non-alcoholic fatty liver disease (NAFLD)-like disease characterised by steatosis, weight gain, insulin resistance and a pro-inflammatory LSEC phenotype, yet LSEC bioenergetics and fenestrae were functionally preserved.…”

Section: Lsec Pathophysiologymentioning

confidence: 99%

The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver

2020

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Liver sinusoidal endothelial cells (LSEC) form a unique barrier between the liver sinusoids and the underlying parenchyma, and thus play a crucial role in maintaining metabolic and immune homeostasis, as well as actively contributing to disease pathophysiology. Whilst their endocytic and scavenging function is integral for nutrient exchange and clearance of waste products, their capillarisation and dysfunction precedes fibrogenesis. Furthermore, their ability to promote immune tolerance and recruit distinct immunosuppressive leukocyte subsets can allow persistence of chronic viral infections and facilitate tumour development. In this review, we present the immunological and barrier functions of LSEC, along with their role in orchestrating fibrotic processes which precede tumourigenesis. We also summarise the role of LSEC in modulating the tumour microenvironment, and promoting development of a pre-metastatic niche, which can drive formation of secondary liver tumours. Finally, we summarise closely inter-linked disease pathways which collectively perpetuate pathogenesis, highlighting LSEC as novel targets for therapeutic intervention.

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Section: Lsec Pathophysiologymentioning

confidence: 99%

The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver

2020

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“…Vascular endothelial growth factor (VGEF), a hormone that functions in blood vessel growth, promotes paracrine signaling from hepatocytes and stellate cells stimulates autocrine signaling of nitric oxide (NO) from LSECs. Animals lacking VEGF tend to exhibit increased defenestration in their LSECs, suggesting that this molecule plays a mechanistic role in either their formation or maintenance (Kus et al, 2019).…”

Section: Lsec Morphologymentioning

confidence: 99%

Prominent Receptors of Liver Sinusoidal Endothelial Cells in Liver Homeostasis and Disease

2020

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Liver sinusoidal endothelial cells (LSECs) are the most abundant non-parenchymal cells lining the sinusoidal capillaries of the hepatic system. LSECs are characterized with numerous fenestrae and lack basement membrane as well as a diaphragm. These unique morphological characteristics of LSECs makes them the most permeable endothelial cells of the mammalian vasculature and aid in regulating flow of macromolecules and small lipid-based structures between sinusoidal blood and parenchymal cells. LSECs have a very high endocytic capacity aided by scavenger receptors (SR), such as SR-A, SR-B (SR-B1 and CD-36), SR-E (Lox-1 and mannose receptors), and SR-H (Stabilins). Other high-affinity receptors for mediating endocytosis include the FcγRIIb, which assist in the antibody-mediated removal of immune complexes. Complemented with intense lysosomal activity, LSECs play a vital role in the uptake and degradation of many blood borne waste macromolecules and small (<280 nm) colloids. Currently, seven Toll-like receptors have been investigated in LSECs, which are involved in the recognition and clearance of pathogen-associated molecular pattern (PAMPs) as well as damage associated molecular pattern (DAMP). Along with other SRs, LSECs play an essential role in maintaining lipid homeostasis with the lowdensity lipoprotein receptor-related protein-1 (LRP-1), in juxtaposition with hepatocytes. LSECs co-express two surface lectins called L-Specific Intercellular adhesion molecule-3 Grabbing Non-integrin Receptor (L-SIGN) and liver sinusoidal endothelial cell lectin (LSECtin). LSECs also express several adhesion molecules which are involved in the recruitment of leukocytes at the site of inflammation. Here, we review these cell surface receptors as well as other components expressed by LSECs and their functions in the maintenance of liver homeostasis. We further discuss receptor expression and activity and dysregulation associated with the initiation and progression of many liver diseases, such as hepatocellular carcinoma, liver fibrosis, and cirrhosis, alcoholic and non-alcoholic fatty liver diseases and pseudocapillarization with aging.

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“…Defenestration of LSECs has been reported in response to alcohol feeding in mice, however in the same study, HFD did not induce changes in fenestration [144]. During NAFLD, LSECs also displayed a pro-inflammatory phenotype, which is central to the activation of HSCs and KCs in the development of fibrosis [140,145].…”

Section: Inflammation and Fibrosis In Hccmentioning

confidence: 79%

“…Interruption of blood flow by tumor cell obstruction of the sinusoidal vasculature can lead to transient ischemia which induces tumoricidal inflammation owing to the release of ROS, nitric oxide (NO), TNF-α and interferon-γ (IFN-γ) by LSECs and KCs [153,155,157]. Similarly, HFD in mice also increased the levels of reactive ROS produced from LSECs [158], and increasing NAFLD severity was associated with a pro-inflammatory gene expression signature in LSECs which included increased COX-2, NOX-2 and IL-6 levels [145]. HFD-induced CLD could therefore potentiate elimination of disseminated tumor cells invading the liver sinusoid.…”

Section: Inflammation In the Microvascular Phase Of Crc Liver Metastasismentioning

confidence: 99%

“…Importantly, adhesion of invading cells to LSECs via E-selectin and ICAM has been well-correlated with development of CRC liver metastasis by stimulating tumor cell extravasation into the Space of Disse [170][171][172][173]. In response to a HFD and with increasing severity of NAFLD, pro-inflammatory cytokines enhanced the expression of adhesion factors E-selectin, ICAM-I and PECAM-I on LSECs [145]. Furthermore, in vitro studies suggest that omega-3 and omega-6 fats obtained from the diet may impact CRC tumor cell adhesion by modulating membrane fatty acid composition and E-selectin expression on LSECs [174], and ultimately increasing liver metastatic burden in vivo [175].…”

Section: Inflammation In the Microvascular Phase Of Crc Liver Metastasismentioning

confidence: 99%

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Inflammation in Primary and Metastatic Liver Tumorigenesis–Under the Influence of Alcohol and High-Fat Diets

2020

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The liver plays an outsized role in oncology. Liver tumors are one of the most frequently found tumors in cancer patients and these arise from either primary or metastatic disease. Hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer and the 6th most common cancer type overall, is expected to become the 3rd leading cause of cancer mortality in the US by the year 2030. The liver is also the most common site of distant metastasis from solid tumors. For instance, colorectal cancer (CRC) metastasizes to the liver in two-thirds of cases, and CRC liver metastasis is the leading cause of mortality in these patients. The interplay between inflammation and cancer is unmistakably evident in the liver. In nearly every case, HCC is diagnosed in chronic liver disease (CLD) and cirrhosis background. The consumption of a Western-style high-fat diet is a major risk factor for the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), both of which are becoming more prevalent in parallel with the obesity epidemic. Excessive alcohol intake also contributes significantly to the CLD burden in the form of alcoholic liver disease (ALD). Inflammation is a key component in the development of all CLDs. Additionally, during the development of liver metastasis, pro-inflammatory signaling is crucial in eliminating invading cancer cells but ironically also helps foster a pro-metastatic environment that supports metastatic seeding and colonization. Here we review how Westernized high-fat diets and excessive alcohol intake can influence inflammation within the liver microenvironment, stimulating both primary and metastatic liver tumorigenesis.

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LSEC Fenestrae Are Preserved Despite Pro-inflammatory Phenotype of Liver Sinusoidal Endothelial Cells in Mice on High Fat Diet

Cited by 40 publications

References 60 publications

The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver

The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver

Prominent Receptors of Liver Sinusoidal Endothelial Cells in Liver Homeostasis and Disease

Inflammation in Primary and Metastatic Liver Tumorigenesis–Under the Influence of Alcohol and High-Fat Diets

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