Fig. 8: Model.
From: Semaphorin-3A regulates liver sinusoidal endothelial cell porosity and promotes hepatic steatosis
Left side: in the setting of low physiological SEMA3A levels (as is the case at low concentrations of saturated fatty acids and normal BW without T2D), active cofilin-1 and normal F-actin cytoskeleton dynamics contribute to maintain a high frequency of fenestrae in LSECs. LSEC porosity facilitates bidirectional exchange of lipids between bloodstream and hepatocytes, such as the release of VLDL particles from hepatocytes into the blood circulation. Right side: in the setting of high SEMA3A levels (as is the case at high concentrations of FFAs and in DIO with or without T2D), the angiocrine signal SEMA3A acts via NRP1 on LSECs to activate multiple STKs, including LIMK1, which phosphorylates cofilin-1 to reduce F-actin cytoskeleton dynamics and fenestrae frequency as well as LSEC porosity. The reduced LSEC porosity lowers VLDL export from the hepatocytes into the blood and might contribute to lipid retention and macrovesicular steatosis in the hepatocytes. The resulting hepatic steatosis is an early event in MASLD that can subsequently (in concert with hepatic stellate cells; HSCs) progress to severe hepatic and cardiometabolic diseases. The figure was created with BioRender.com.
