The endothelial dysfunction blocker CU06-1004 ameliorates choline-deficient L-amino acid diet-induced non-alcoholic steatohepatitis in mice

Abstract

Non-alcoholic steatohepatitis (NASH) is a severe, advanced form of non-alcoholic fatty liver disease (NAFLD) that is associated with features of metabolic syndrome and characterized by hepatic steatosis, inflammation, and fibrosis. In addition, NASH is associated with endothelial dysfunction within the hepatic vasculature. Treatment with CU06-1004 (previously called Sac-1004) ameliorates endothelial dysfunction by inhibiting hyperpermeability and inflammation. In this study, we investigated the protective effects of CU06-1004 in a choline-deficient L-amino acid (CDAA)-induced mouse model of NASH for 3 or 6 weeks. Specifically, we evaluated the effects of CU06-1004 on lipid accumulation, inflammation, hepatic fibrosis, and liver sinusoidal endothelial cell (LSEC) capillarization through biochemical analysis, immunohistochemistry, and real-time PCR. We found that the administration of CU06-1004 to mice improved liver triglyceride (TG) and serum alanine aminotransferase (ALT) in this CDAA-induced model of NASH for 6 weeks. In groups of NASH induced mice for both 3 and 6 weeks, CU06-1004 significantly reduced the hepatic expression of genes related to lipogenesis, inflammation, and cell adhesion. However, expression of genes related to hepatic fibrosis and vascular endothelial changes were only decreased in animals with mild NASH. These results suggest that the administration of CU06-1004 suppresses hepatic steatosis, inflammation, fibrosis, and LSEC capillarization in a CDAA-induced mouse model of NASH. This suggests that CU06-1004 has therapeutic potential for the treatment of mild NASH.

Choline supplements: An update

“…Endothelial cells play a crucial role in the exchange of choline and other nutrients between plasma and brain tissue ( 75 , 106 – 108 ). Thus, choline must be incorporated into endothelial cells to be transported to the blood-brain barrier ( 109 ).…”

The Pathophysiological Associations Between Obesity, NAFLD, and Atherosclerotic Cardiovascular Diseases

“…E-selectin is a biomarker of endothelial dysfunction and mediates inflammatory cell adhesion and tissue infiltration [171]. Consistently, improving endothelial function by CU06-1004 ameliorated endothelial dysfunction by decreasing hyperpermeability and inflammation, attenuated hepatic steatosis, inflammation, fibrosis, and liver sinusoidal epithelial cells capillarization in the mice model of NAFLD/NASH [172].…”

Liver sinusoidal endothelial cells as potential drivers of liver fibrosis (Review)

“…Based on a specific route of drug delivery targeting LSECs, strategies that reverse endothelial dysfunction by inhibiting Notch signaling ( 30 , 101 ) and Hh signaling ( 102 , 103 ), downregulating VEGF-R2 ( 104 ), or suppressing KLF5-mediated LSEC angiogenesis ( 105 ), inhibiting hypoxia-inducible factor-1α (HIF-1α) ( 106 ) or enhancing endothelial barrier function through the cyclic adenosine monophosphate/Rac/cortactin pathway ( 107 ), can be applied to improve liver fibrosis. Besides special targeting of LSECs, there are other methods of liver fibrosis treatment that act via an indirect effect on LSECs, such as simultaneous consumption of LSECs and aHSCs ( 108 ), artificial control of the switch of the Erk1/2-Akt axis in LSECs to reverse LSECs from a proregenerative to a profibrotic phenotype ( 53 ), prevention of interstellar interaction of LSECs ( 109 , 110 ), selective enhancement of autophagy in LSEC in the early stages ( 111 ) and treatment of liver fibrosis with anti-angiogenic agents ( 112 ).…”