Abstract
Vascular protein sorting-associated protein 33B (VPS33B) plays important roles in hepatic polarity, which directly maintains the functional structure of the liver. It has reported that VPS33B has close association with arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome. Unfortunately, no further studies were conducted to reveal the role of Vps33b in the homeostasis of bile acids. In the current study, hepatic Vps33b-depleted male mice were used to investigate the metabolomics and lipidomics profiles of hepatic Vps33b deficiency based on ultrahigh-performance liquid chromatography coupled with an electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS) system. Hepatic Vps33b-depleted male mice displayed cholestasis and slight liver damage with increased serum levels of ALT, AST, ALP and T-Bili compared to wild-type mice. Targeted metabolomics analysis of bile acids revealed that increased taurine-conjugated bile acids accumulated in the serum of hepatic Vps33b-depleted mice, while unconjugated bile acids were prone to decrease, accompanied by the regulation of bile acid homeostasis-related genes. In addition, lipid profiles were significantly altered with the lack of Vps33b in the liver. A variety of lipids, such as triglycerides and sphingomyelins, were significantly decreased in the liver and increased in the serum of hepatic Vps33b-depleted mice compared to those in wild-type mice. Our study demonstrated that Vps33b influences the progress of liver metabolism both in bile acid circulation and lipid metabolism, which is involved in the progression of liver cholestasis in mice.
Highlights
Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (OMIM 208085), an autosomal recessive multiorgan disorder that was originally described in 1973 by LutzRichner typically presents with neurogenic arthrogryposis, multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia
Histological analysis showed hepatocyte degeneration, necrosis and ductal proliferation around the portal area in Vps33bflox/flox, alb-cre mice (Figure 2). These results indicated that hepatic Vps33b knockout mice displayed cholestasis and slight liver injury compared to Vps33bflox/flox mice
ARC syndrome, caused by Vascular protein sorting-associated protein 33B (VPS33B) mutations, is a disease involving in multiple organs with a variety of clinical features (Cullinane et al, 2009), and alternative diagnostic approaches should be suggested to replace organ biopsies as a first-line diagnostic test for most children who are suspected to have ARC syndrome (Gissen et al, 2006)
Summary
Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (OMIM 208085), an autosomal recessive multiorgan disorder that was originally described in 1973 by LutzRichner typically presents with neurogenic arthrogryposis, multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia. This disorder mostly affects the offspring of consanguineous unions, where patients usually die within a few months of birth (Horslen et al, 1994). VPS33B, a 617 AA protein of the Sec-1/Muc (SM) family (Huizing et al, 2001), is involved in the vesicular intracellular trafficking process and protein interactions (Chen C.H. et al, 2017). The general role of these proteins in membrane trafficking demonstrated the vital role of Vps33b in intracellular trafficking functions
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