Liver Aging and Pseudocapillarization in a Werner Syndrome Mouse Model

Abstract

Werner syndrome is a progeric syndrome characterized by premature atherosclerosis, diabetes, cancer, and death in humans. The knockout mouse model created by deletion of the RecQ helicase domain of the mouse Wrn homologue gene (Wrn(∆hel/∆hel)) is of great interest because it develops atherosclerosis and hypertriglyceridemia, conditions associated with aging liver and sinusoidal changes. Here, we show that Wrn(∆hel/∆hel) mice exhibit increased extracellular matrix, defenestration, decreased fenestration diameter, and changes in markers of liver sinusoidal endothelial cell inflammation, consistent with age-related pseudocapilliarization. In addition, hepatocytes are larger, have increased lipofuscin deposition, more frequent nuclear morphological anomalies, decreased mitochondria number, and increased mitochondrial diameter compared to wild-type mice. The Wrn(∆hel/∆hel) mice also have altered mitochondrial function and altered nuclei. Microarray data revealed that the Wrn(∆hel/∆hel) genotype does not affect the expression of many genes within the isolated hepatocytes or liver sinusoidal endothelial cells. This study reveals that Wrn(∆hel/∆hel) mice have accelerated typical age-related liver changes including pseudocapillarization. This confirms that pseudocapillarization of the liver sinusoid is a consistent feature of various aging models. Moreover, it implies that DNA repair may be implicated in normal aging changes in the liver.

Mitochondrial ultrastructure and markers of dynamics in hepatocytes from aged, calorie restricted mice fed with different dietary fats

“…In regard to mitochondria, it has been reported that aging results in increased mitochondrial size (see Le Couteur et al, 2010) and in some cases this increase can be accompanied by modification of cristal morphology (Sastre et al, 1996). These changes have been confirmed in mice with different progeroid syndromes (Cogger et al, 2013; Gregg et al, 2012) strengthening the idea of increased mitochondrial size during aging.…”

“…that have implications for many diseases (Cogger et al, 2013; Gregg et al, 2012; Le Couteur et al, 2010). However, in this work we have only considered hepatocytes showing a typical morphology similar to that described in the literature (see for example, Pieri et al, 1980; Schmucker, 1990) and possible modifications on cell types other than hepatocytes have not been analyzed.…”

“…In some cases these changes appear after a few weeks of the intervention, denoting a quick adaptation of the mitochondria compartment to the conditions induced by these interventions. In spite of some contradictory data (see Pieri et al, 1980), it is assumed that aging results in a decreased number of mitochondria in hepatocytes (Sastre et al, 1996; Schmucker et al, 1978), an effect that has also been observed in progeroid Werner mice (Cogger et al, 2013). Conversely, CR has been reported to induce a significant increase in the number of mitochondria per cell (López-Lluch et al, 2006).…”

Characterization of the Expression and Function of the C-Type Lectin Receptor CD302 in Mice and Humans Reveals a Role in Dendritic Cell Migration

“…Activated B cells, DC, and Mf for transcription studies were cultured for 4 h in complete RPMI (RPMI 1640 with 10% FCS, 2 mM GlutaMAX, 100 U/ml penicillin, 100 mg/ml streptomycin, 1 mM sodium pyruvate, 10 mM HEPES, and 50 mM 2-ME from Thermo Fisher) with 1 mg/ml LPS (Escherichia coli K12, InvivoGen), and T cells with a 1:1 ratio of mouse T-Activator CD3/28 Dynabeads (Thermo Fisher). To isolate hepatocytes, LSEC, and KC for transcriptional analysis, livers of WT or KO mice were perfused with collagenase III and extracted as previously described (16,17). The resulting liver cell suspension was twice centrifuged at 54 3 g to pellet hepatocytes, and the residual supernatant was layered on a two-step Percoll gradient (25-50%) …”

Systemic VEGF-A Neutralization Ameliorates Diet-Induced Metabolic Dysfunction

“…Hepatic sinusoidal fenestrations were measured in perfused livers by scanning electron microscopy as recently described (31).…”