Non-alcoholic fatty liver disease and its related complications are becoming one of the most important health problems globally. The liver functions as both a metabolic and an immune organ. The crosstalk between hepatocytes and intrahepatic immune cells plays a key role in coordinating a dual function of the liver in terms of the protection of the host from antigenic overload as a result of receiving nutrients and gut microbiota antigenic stimulation via facilitating immunologic tolerance. B cells are the most abundant lymphocytes in the liver. The crucial role of intrahepatic B cells in energy metabolism under different immune conditions is now emerging in the literature. The accumulating evidence has demonstrated that the antibodies and cytokines produced by B cells in the microenvironment play key and distinct roles in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Herein, we have aimed to consolidate and update the current knowledge about the pathophysiological roles of B cells as well as the underlying mechanisms in energy metabolism. Understanding how B cells can exacerbate and suppress liver damage by exploiting the antibodies and cytokines they produce will be of great importance for designing B-cell targeting therapies to treat various liver diseases.

Background:Recent research has shown that the G protein-coupled receptor 110 (GPR110) is an oncogene. The evidence mainly based on high expression of GPR110 in numerous cancer types; and knockdown GPR110 can reduced the cell migration, invasion, and proliferation. GPR110 is, however, mostly expressed in the liver of healthy individuals. The function of GPR110 in liver has not been revealed. Interestingly, expression level of hepatic GPR110 is dramatically decreased in obese subjects. Here, we examined whether GPR110 has a role in liver metabolism.Methods:We used recombinant adeno-associated virus-mediated gene delivery system and antisense oligonucleotide to manipulate the hepatic GPR110 expression level in diet-induced obese mice to investigate the role of GPR110 in hepatic steatosis. The clinical relevance was examined using transcriptome profiling and archived biopsy specimens of liver tissues from non-alcoholic fatty liver disease (NAFLD) patients with different degree of fatty liver.Results:The expression of GPR110 in the liver was directly correlated to fat content in the livers of both obese mice and NAFLD patients. Stearoyl-coA desaturase 1 (SCD1), a crucial enzyme in hepatic de novo lipogenesis, was identified as a downstream target of GPR110 by RNA-sequencing analysis. Treatment with the liver-specific SCD1 inhibitor MK8245 and specific shRNAs against SCD1 in primary hepatocytes improved the hepatic steatosis of GPR110-overexpressing mice and lipid profile of hepatocytes, respectively.Conclusions:These results indicate GPR110 regulates hepatic lipid metabolism through controlling the expression of SCD1. Down-regulation of GPR110 expression can potentially serve as a protective mechanism to stop the over-accumulation of fat in the liver in obese subjects. Overall, our findings not only reveal a new mechanism regulation the progression of NALFD, but also proposed a novel therapeutic approach to combat NAFLD by targeting GPR110.Fundings: This work was supported in part by National Natural Science Foundation of China 81870586 (CMW), 82270941 and 81974117 (JS), Area of Excellence AoE/M-707/18 (AX and CMW), and General Research Fund 15101520 (CMW).

Background:Recent research has shown that the adhesion G protein-coupled receptor F1 (Adgrf1; also known as GPR110; PGR19; KPG_012; hGPCR36) is an oncogene. The evidence is mainly based on high expression of Adgrf1 in numerous cancer types, and knockdown Adgrf1 can reduce the cell migration, invasion, and proliferation. Adgrf1 is, however, mostly expressed in the liver of healthy individuals. The function of Adgrf1 in liver has not been revealed. Interestingly, expression level of hepatic Adgrf1 is dramatically decreased in obese subjects. Here, the research examined whether Adgrf1 has a role in liver metabolism.Methods:We used recombinant adeno-associated virus-mediated gene delivery system, and antisense oligonucleotide was used to manipulate the hepatic Adgrf1 expression level in diet-induced obese mice to investigate the role of Adgrf1 in hepatic steatosis. The clinical relevance was examined using transcriptome profiling and archived biopsy specimens of liver tissues from non-alcoholic fatty liver disease (NAFLD) patients with different degree of fatty liver.Results:The expression of Adgrf1 in the liver was directly correlated to fat content in the livers of both obese mice and NAFLD patients. Stearoyl-coA desaturase 1 (Scd1), a crucial enzyme in hepatic de novo lipogenesis, was identified as a downstream target of Adgrf1 by RNA-sequencing analysis. Treatment with the liver-specific Scd1 inhibitor MK8245 and specific shRNAs against Scd1 in primary hepatocytes improved the hepatic steatosis of Adgrf1-overexpressing mice and lipid profile of hepatocytes, respectively.Conclusions:These results indicate Adgrf1 regulates hepatic lipid metabolism through controlling the expression of Scd1. Downregulation of Adgrf1 expression can potentially serve as a protective mechanism to stop the overaccumulation of fat in the liver in obese subjects. Overall, the above findings not only reveal a new mechanism regulating the progression of NAFLD, but also proposed a novel therapeutic approach to combat NAFLD by targeting Adgrf1.Funding:This work was supported by the National Natural Science Foundation of China (81870586), Area of Excellence (AoE/M-707/18), and General Research Fund (15101520) to CMW, and the National Natural Science Foundation of China (82270941, 81974117) to SJ.

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