Neutral Ceramidase Mediates Nonalcoholic Steatohepatitis by Regulating Monounsaturated Fatty Acids and Gut IgA+ B Cells

Abstract

Background and Aims Nonalcoholic steatohepatitis (NASH) is associated with obesity and an increased risk for liver cirrhosis and cancer. Neutral ceramidase (NcDase), which is highly expressed in the intestinal brush border of the small intestine, plays a critical role in digesting dietary sphingolipids (ceramide) to regulate the balance of sphingosine and free fatty acids. It remains unresolved whether obesity‐associated alteration of NcDase contributes to the manifestation of NASH. Here, we revealed that NcDase deficiency in murine models of NASH prevents hepatic inflammation and fibrosis but not steatosis. Approach and Results NcDase−/− mice display reduced stearoyl‐CoA desaturase (SCD) 1 expression with a compositional decrease of monounsaturated fatty acids (MUFAs) under the different dietary conditions. We further found that NcDase is a functional regulator of intestinal B cells and influences the abundance and quality of the secretory IgA response toward commensal bacteria. Analysis of composition of the gut microbiota found that Clostridiales colonization was increased in NcDase−/− mice. The colonization of germ‐free mice with gut microbiota from NcDase−/− mice resulted in a greater decrease in the expression of SCD1 and the level of MUFAs in the liver relative to gut microbiota from wild‐type littermates, which are associated with the alternation of IgA‐bound bacteria, including increase of Ruminococcaceae and reduction of Desulfovibrio. Mechanistically, NcDase is a crucial link that controls the expression of SCD1 and MUFA‐mediated activation of the Wnt/β‐catenin. Very importantly, our experiments further demonstrated that Wnt3a stimulation can enhance the activity of NcDase in hepatocytes. Conclusions Thus, the NcDase‐SCD1‐Wnt feedback loop promotes the diet‐induced steatohepatitis and fibrosis through the regulation of intestinal IgA+ immune cells.

RETRACTED: Pyrvinium Treatment Confers Hepatic Metabolic Benefits via β-Catenin Downregulation and AMPK Activation

“…β-catenin plays an important role in regulation of hepatic glucose and lipid metabo lism. It has been reported that fatty acid treatment will lead to β-catenin accumulation in hepatocytes, which enhances lipogenesis, eventually causing steatohepatitis [33]. Consist ently, under a high fat diet, hepatocyte-specific β-catenin transgenic (TG) mice showed apparent steatosis, as well as rapid obesity and systemic insulin resistance in comparison to wild-type mice.…”

Astragali Radix–Codonopsis Radix–Jujubae Fructus water extracts ameliorate exercise‐induced fatigue in mice via modulating gut microbiota and its metabolites

“…In addition, fecal sphingosine was negatively correlated with the abundance of Desulfovibrio , which suggesting the close relationship between Desulfovibrio and sphingolipid metabolism. It was also reported that the deficiency of neutral ceramidase (NcDase), which was the key enzyme of sphingolipid metabolism and highly expressed in the small intestine and colon, could result in reduction of Desulfovibrio 49 . Streptococcus is one of bacteria which producing d ‐lactic acid in the gut, 50 and was reported increased significantly in the fecal samples of CFS patients 51 .…”

“…It was also reported that the deficiency of neutral ceramidase (NcDase), which was the key enzyme of sphingolipid metabolism and highly expressed in the small intestine and colon, could result in reduction of Desulfovibrio. 49 Streptococcus is one of bacteria which producing D-lactic acid in the gut, 50 and was reported increased significantly in the fecal samples of CFS patients. 51 In this study, the abundance of Streptococcus was reduced in the high group, suggesting ACJ could suppress the LA production to increase exercise endurance.…”

Liver Fibrosis and MAFLD: From Molecular Aspects to Novel Pharmacological Strategies

“…Stearoyl-CoA desaturase 1 (SCD1) is also a key enzyme for hepatic lipid anabolism that catalyzes the rate-limiting step of converting saturated fatty acids into monounsaturated fatty acids (63). Studies have indicated that SCD1 is overexpressed in activated HSCs, and is involved in diet-induced steatohepatitis and fibrosis by regulating Wnt signaling (64,65). Decreasing SCD1 expression through genetic disruption or pharmacological inhibition reduced HSCs activation and alleviated liver fibrosis and steatohepatitis in murine models (66,67).…”