Alterations in liver sinusoidal endothelium in a baboon model of type 1 diabetes

Abstract

Aims/hypothesis Diabetes mellitus is associated with extensive vascular pathology, yet little is known about its longterm effects on liver sinusoidal endothelial cells (LSECs).Potential diabetic changes in LSECs are important because of the role played by fenestrations in the LSECs in hepatic disposition of lipoproteins. Materials and methods Surgical liver biopsies for electron microscopy and immunohistochemistry were obtained from baboons with long-standing streptozotocin-induced, insulin-treated diabetes mellitus and compared with those from age-matched control animals. Results There was an increase in the thickness of LSECs (170±17 vs 123±10 nm, p<0.01). Fenestrations in LSECs, as determined by overall porosity, were markedly reduced (1.4±0.1% vs 2.6±0.2%, p<0.01). Increased numbers of stellate cells were seen on electron microscopy, and this finding was corroborated by increased smooth muscle actin expression. Diabetes mellitus was also associated with increased endothelial production of von Willebrand factor and caveolin-1. Conclusions/interpretation Diabetes mellitus in the nonhuman primate is associated with marked changes in LSECs, including a reduction in fenestrations. Such changes provide an additional and novel mechanism for impaired hepatic lipoprotein clearance and post-prandial hyperlipidaemia in diabetes mellitus.

Diabetes is a progression factor for hepatic fibrosis in a high fat fed mouse obesity model of non-alcoholic steatohepatitis

“…glucosuric agents) in the HFD + DM group will be required to address whether the CTGF dysregulation and liver fibrosis observed depend on the diabetic range blood glucose levels occurring in the model. CTGF has been implicated by us [21,22,47] and others [48][49][50] in the process of diabetic tissue fibrosis, including the induction of TIMP-1 in renal diabetes [21]. In the current model, CTGF mRNA and more predominantly CTGF protein were elevated by the combination of HFD and diabetes and the CTGF mRNA correlated with collagen-I, collagen-III, and TIMP-1 mRNA in HFD + DM.…”

Genetic Evidence Supporting a Critical Role of Endothelial Caveolin-1 during the Progression of Atherosclerosis

“…8b and 8c). The idea that Cav-1 regulates SEC porosity is supported by the correlation between sinusoid pseudocapillarization and the levels of hepatic Cav-1 (Jamieson et al, 2007). Thus, the reduced clearance of TG in ApoE −/− Cav-1 −/− mice is likely due to pseudocapillarization of the SEC.…”

The response of fenestrations, actin, and caveolin-1 to vascular endothelial growth factor in SK Hep1 cells

“…The results obtained illustrate that the transfected SK Hep1 cells provide a valuable tool for the identification of novel modulators of fenestrations. Agents that increase porosity may have a role in the management of dyslipidemia associated with old age (21,31) and diabetes mellitus (25), where loss of fenestrations prevents the transfer of lipoproteins into the hepatocytes.…”