IDDF2024-ABS-0143 Adipocyte SQLE attenuated NAFLD via multi-organ ceramide homeostasis disorder and is a therapeutic target

<h3>Background</h3> Obesity is a critical risk factor for Non-alcoholic fatty liver disease (NAFLD); however, the role of adipose tissue in obesity-related NAFLD is unclear. Squalene epoxidase (SQLE) is a rate-limiting enzyme of cholesterol biosynthesis. Here, we report that adipocyte SQLE suppresses NAFLD development. Proline supplementation ameliorated NAFLD by stabilizing white adipocyte SQLE protein expression. <h3>Methods</h3> Whole-body knockout SQLE mice, adipocyte-specific overexpression and knockout SQLE transgenic mice were generated by the company and fed with a CD-HFD diet to induce NAFLD. Lipid metabolomics was used to analyze and screen the differential metabolites in epididymal white adipose tissue (eWAT), serum and liver affected by adipocyte SQLE knockout. HE staining and Oil Red O staining were used to evaluate the liver histopathology. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and insulin tolerance test (ITT) were also detected to evaluate liver injury. <h3>Results</h3> Hepatocyte-specific knockout of SQLE significantly attenuates the progression of NAFLD, while whole-body knockout of SQLE markedly aggravated liver steatosis (IDDF2024-ABS-0143 Figure 1. Whole-body knockout of SQLE markedly aggravated liver steatosis), suggesting organ differences in the effects of SQLE. Consistent with this finding, western blot analysis showed that eWAT SQLE was down-regulated in mouse NAFLD models fed with CD-HFD fed. Adipocyte-specific SQLE knockout accelerates CD-HFD diet-induced liver steatosis and injury. While adipocyte-specific SQLE overexpression ameliorated CD-HFD diet induced NAFLD (IDDF2024-ABS-0143 Figure 2. Adipocyte SQLE overexpression attenuates diet-induced NAFLD). Mechanistically, adipocyte SQLE suppresses NAFLD development via HIF2α/ACER2-regulated ceramide homeostasis between adipose tissue, serum, and liver tissue (IDDF2024-ABS-0143 Figure 3. Adipocyte SQLE suppresses NAFLD development via HIF2α/ACER2-regulated ceramide homeostasis). Interestingly, supplementary proline, which is down-regulated in the serum of NAFLD patients, can stabilize the protein expression of SQLE in white adipose tissue, decrease serum ceramide concentration, and improve the progression of NAFLD (IDDF2024-ABS-0143 Figure 4. Proline supplementation alleviated NAFLD by activating protein expression of eWAT). <h3>Conclusions</h3> These data demonstrated that abnormal cholesterol metabolism in white adipose tissue is an important ‘extrahepatic strike’ in the development of NAFLD. Adipocyte SQLE active HIF2α/ACER2 signal, increases adipocyte ceramide degradation and disturbs ceramide homeostasis, thereby reducing liver cholesterol and triglyceride accumulation and improving NAFLD. Targeted activation of adipose tissue SQLE is a promising therapeutic strategy for NAFLD treatment.