Abstract
The porosity of liver sinusoidal endothelial cells (LSEC) ensures bidirectional passive transport of lipoproteins, drugs and solutes between the liver capillaries and the liver parenchyma. This porosity is realized via fenestrations – transcellular pores with diameters in the range of 50–300 nm – typically grouped together in sieve plates. Aging and several liver disorders severely reduce LSEC porosity, decreasing their filtration properties. Over the years, a variety of drugs, stimulants, and toxins have been investigated in the context of altered diameter or frequency of fenestrations. In fact, any change in the porosity, connected with the change in number and/or size of fenestrations is reflected in the overall liver-vascular system crosstalk. Recently, several commonly used medicines have been proposed to have a beneficial effect on LSEC re-fenestration in aging. These findings may be important for the aging populations of the world. In this review we collate the literature on medicines, recreational drugs, hormones and laboratory tools (including toxins) where the effect LSEC morphology was quantitatively analyzed. Moreover, different experimental models of liver pathology are discussed in the context of fenestrations. The second part of this review covers the cellular mechanisms of action to enable physicians and researchers to predict the effect of newly developed drugs on LSEC porosity. To achieve this, we discuss four existing hypotheses of regulation of fenestrations. Finally, we provide a summary of the cellular mechanisms which are demonstrated to tune the porosity of LSEC.
Highlights
Within the human body, the main blood-organ barrier is made up of a single layer of thin endothelial cells
Drug clearance mediated by the liver is heavily dependent on the proper phenotype of Liver sinusoidal endothelial cells (LSEC), including the transport through fenestrations
Individual drugs and stimulants have been reported to influence the porosity of LSEC
Summary
The main blood-organ barrier is made up of a single layer of thin endothelial cells. LSEC in old age have markedly reduced porosity (percent of the cell surface area covered in fenestrations) by about 50% – in other words, old LSEC become “defenestrated” (Figure 2) This defenestration results in hampered bi-directional traffic of substrates between the blood and the hepatocytes. Given the vital role of LSEC fenestrations (and the bidirectional flow of substrates through them) in physiology and homeostasis, a better understanding of how these structures are regulated will enable us to design novel therapeutic approaches targeting biological changes of aging and liver diseases It needs to be highlighted, that many reports in the literature “suffer” from developing experimental methodologies. Ethanol at any dose does not appear to improve LSEC porosity but rather has the opposite effect
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