Go with the flow: Hemodynamic changes affect liver ultrastructure

Heart failure (HF) is one of the leading causes of death in the Western world, and it is estimated that in the United States approximately 1 in 4 persons will develop HF in their lifetime.¹ Among the comorbidities associated with HF, various liver pathologies² will have major consequences for HF patients in the longer term, likely creating a vicious circle further exacerbating the disease. Kamila Wojnar-Lason et al. (2024—this issue of Acta Physiologica) report an interesting effect of chronic HF on liver ultrastructure in Tgαq*44 mice that develop progressive right ventricle dysfunction with aging.³ Elegantly using a range of super-resolution microscopy methods including atomic force microscopy (AFM), transmission electron microscopy (TEM), and scanning EM (SEM), Wojnar-Lason et al. show that fenestrated liver sinusoidal endothelial cells (LSEC) in Tgαq*44 mice have reductions in their fenestration frequency and diameter. LSEC fenestrations are patent nanopores that are conduits for the bidirectional transfer of solutes between the plasma and the hepatocytes, and their loss (termed “defenestration”) negatively affects liver function, including the clearance of lipoproteins from the circulation.

The use of AFM to examine LSEC fenestrations was pioneered by Braet, Wisse et al.⁴ The Chlopicki laboratory, in collaboration with the laboratories of Prof. Marek Szymonski (Jagiellonian University, Poland) and Dr. Bartlomiej Zapotoczny (Institute of Nuclear Physics, Polish Academy of Sciences), took this method on board and have since published numerous elegant AFM studies elucidating the ultrastructure of these nanopores.^5-9 In the present study, Chlopicki and colleagues also understood the need to include more “classic” methodologies, namely TEM and SEM, to demonstrate LSEC defenestration in situ within Tgαq*44 mice. Using these EM methods, Wojnar-Lason et al. produced clear and thoroughly convincing results, and the use of multiple/difficult methodologies in this study is highly commendable. Worthy of extra mention—the SEM images of liver sinusoids in figure 3 are a pleasure to behold, and clearly demonstrate that chronic HF causes defenestration in the Tgαq*44 model.

During ageing, age-related LSEC defenestration likely impairs the passage of insulin from the plasma to the hepatocytes contributing to age-related insulin resistance.¹⁰ In addition, age-related LSEC defenestration is now accepted as a significant factor in age-related hyperlipidaemia.¹¹ In concordance with this, Wojnar-Lason et al. also noted prolonged postprandial hypertriglyceridemia in the Tgαq*44 model in 4-month-old mice and elevated LDL levels in the 12-month-old mice. The findings of Wojnar-Lason and colleagues—demonstrating that chronic HF causes LSEC defenestration—suggest that chronic HF-induced LSEC defenestration will come on top of age-related defenestration that occurs across a number of mammalian species, including humans.¹² This “extra” HF-induced defenestration would potentially start a vicious cycle whereby chronic HF reduces lipid clearance (via LSEC fenestrations) causing more hyperlipidemia and thereby further increasing risk factors for HF and/or exacerbating existing HF disease. Interestingly, there are interventions that can potentially reverse age-related defenestration that could also be relevant in this HF context.^13-15

In the current paper, Wojnar-Lason et al. investigated other known LSEC properties, in particular, LSEC-mediated scavenging of waste macromolecules.¹⁶ LSEC are voracious scavengers of wastes/colloids <200 nm in diameter, and this aspect of LSEC is largely ignored by the hepatology field. I therefore also commend the authors for looking at this aspect in the Tgαq*44 mice. Interestingly, the authors found no differences in LSEC-mediated Ac-LDL scavenging in Tgαq*44 vs. control mice, but this is likely the result of using a fluorescence-based assay with trace amounts of Ac-LDL ligand. Capacity studies, similar to those of Simon-Santamaria et al.¹⁷ using saturating amounts of ligand and more precise quantitative methods, for example, using a radiolabeled ligand, might have revealed differences in LSEC-mediated scavenging between the 2 groups.

The authors reported a number of other changes in various parameters in Tgαq*44 mice, such as age-dependent differences in albumin and bilirubin production, blood lipids, and dramatically increased gamma-glutamyl transferase in 12-month-old mice, but (to my mind) the chronic HF-mediated defenestration of LSEC is the most striking and has the greatest implications on physiology. This study elegantly demonstrates that hemodynamic changes caused by chronic HF can have profound negative effects on LSEC ultrastructure. It, therefore, raises the question, will other cardiac disorders (e.g., arrhythmias) also cause similar disruptions in LSEC structure and function?

The author has no conflicts of interest to declare.