LY6D is crucial for lipid accumulation and inflammation in nonalcoholic fatty liver disease
2
조회
0
다운로드
0
인용
0
참고문헌
초록
Nonalcoholic fatty liver disease (NAFLD) is a serious metabolic disorder characterized by excess fat accumulation in the liver. Over the past decade, NAFLD prevalence and incidence have risen globally. There are currently no effective licensed drugs for its treatment. Thus, further study is required to identify new targets for NAFLD prevention and treatment. In this study, we fed C57BL6/J mice one of three diets, a standard chow diet, high-sucrose diet, or high-fat diet, and then characterized them. The mice fed a high-sucrose diet had more severely compacted macrovesicular and microvesicular lipid droplets than those in the other groups. Mouse liver transcriptome analysis identified lymphocyte antigen 6 family member D (Ly6d) as a key regulator of hepatic steatosis and the inflammatory response. Data from the Genotype-Tissue Expression project database showed that individuals with high liver Ly6d expression had more severe NAFLD histology than those with low liver Ly6d expression. In AML12 mouse hepatocytes, Ly6d overexpression increased lipid accumulation, while Ly6d knockdown decreased lipid accumulation. Inhibition of Ly6d ameliorated hepatic steatosis in a diet-induced NAFLD mouse model. Western blot analysis showed that Ly6d phosphorylated and activated ATP citrate lyase, which is a key enzyme in de novo lipogenesis. In addition, RNA- and ATAC-sequencing analyses revealed that Ly6d drives NAFLD progression by causing genetic and epigenetic changes. In conclusion, Ly6d is responsible for the regulation of lipid metabolism, and inhibiting Ly6d can prevent diet-induced steatosis in the liver. These findings highlight Ly6d as a novel therapeutic target for NAFLD.
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a serious metabolic disorder characterized by excess fat accumulation in the liver. Over the past decade, NAFLD prevalence and incidence have risen globally. There are currently no effective licensed drugs for its treatment. Thus, further study is required to identify new targets for NAFLD prevention and treatment. In this study, we fed C57BL6/J mice one of three diets, a standard chow diet, high-sucrose diet, or high-fat diet, and then characterized them. The mice fed a high-sucrose diet had more severely compacted macrovesicular and microvesicular lipid droplets than those in the other groups. Mouse liver transcriptome analysis identified lymphocyte antigen 6 family member D (Ly6d) as a key regulator of hepatic steatosis and the inflammatory response. Data from the Genotype-Tissue Expression project database showed that individuals with high liver Ly6d expression had more severe NAFLD histology than those with low liver Ly6d expression. In AML12 mouse hepatocytes, Ly6d overexpression increased lipid accumulation, while Ly6d knockdown decreased lipid accumulation. Inhibition of Ly6d ameliorated hepatic steatosis in a diet-induced NAFLD mouse model. Western blot analysis showed that Ly6d phosphorylated and activated ATP citrate lyase, which is a key enzyme in de novo lipogenesis. In addition, RNA- and ATAC-sequencing analyses revealed that Ly6d drives NAFLD progression by causing genetic and epigenetic changes. In conclusion, Ly6d is responsible for the regulation of lipid metabolism, and inhibiting Ly6d can prevent diet-induced steatosis in the liver. These findings highlight Ly6d as a novel therapeutic target for NAFLD.
참고문헌 (63)
- Hashimoto, E., "Characteristics and diagnosis of NAFLD", NASH, 2013, pp.28, 64~70
- Adams, L. A., "Nonalcoholic fatty liver disease", CMAJ, 172, pp.899~905 (2005)
- Mantovani, A., "Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers : a meta-analysis of observational cohort studies", Gut, 71, pp.778~788 (2022)
- Mantovani, A., "Non-alcoholic fatty liver disease and risk of incident chronic kidney disease : an updated meta-analysis", Gut, 71, pp.156~162 (2022)
- Riazi, K., "The prevalence and incidence of NAFLD worldwide : a systematic review and meta-analysis", Lancet Gastroenterol. Hepatol, 7, pp.851~861 (2022)
- Pouwels, S., "Non-alcoholic fatty liver disease(NAFLD) : a review of pathophysiology, clinical management and effects of weight loss", BMC Endocrine Disorders, 22, pp.1~9 (2022)
- Friedman, S. L., "Mechanisms of NAFLD development and therapeutic strategies", Nat. Med, 24, pp.908~922 (2018)
- Van Herck, M. A., "Animal models of nonalcoholic fatty liver disease—a starter’s guide", Nutrients, 9, pp.1072~ (2017)
- Lian, C. Y., "High fat diet-triggered non-alcoholic fatty liver disease : a review of proposed mechanisms", Chem. Biol. Interact, 330, pp.109199~ (2020)
- Eng, J. M., "Diet-induced models of non-alcoholic fatty liver disease:food for thought on sugar, fat, and cholesterol", Cells, 10, pp.1805~ (2021)
- Ishimoto, T., "High-fat and high-sucrose(western)diet induces steatohepatitis that is dependent on fructokinase", Hepatology, 58, pp.1632~1643 (2013)
- Lee, P. Y., "Ly6 family proteins in neutrophil biology", J. Leukocyte Biol, 94, pp.585~594 (2013)
- Upadhyay, G., "Emerging role of lymphocyte antigen-6 family of genes in cancer and immune cells", Front. Immunol, 10, pp.819~ (2019)
- Nagano, T., "LY6D-induced macropinocytosis as a survival mechanism of senescent cells", J. Biol. Chem, 296, pp.100049~ (2021)
- Krämer, A., "Causal analysis approaches in ingenuity pathway analysis", Bioinformatics, 30, pp.523~530 (2014)
- Abd El-Kader, S. M., "Non-alcoholic fatty liver disease : the diagnosis and management", World J. Hepatol, 7, pp.846~858 (2015)
- Kotronen, A., "Hepatic stearoyl-CoA desaturase(SCD)-1 activity and diacylglycerol but not ceramide concentrations are increased in the nonalcoholic human fatty liver", Diabetes, 58, pp.203~208 (2009)
- Aljohani, A., "Hepatic Stearoyl-CoA desaturase-1 deficiency-mediated activation of mTORC1-PGC-1alpha axis regulates ER stress during high-carbohydrate feeding", Sci. Rep, 9, pp.15761~ (2019)
- Ma, H. P., "Collagen 1A1(COL1A1)is a reliable biomarker and putative therapeutic target for hepatocellular carcinogenesis and metastasis", Cancers(Basel), 11, pp.786~ (2019)
- Miyazaki, H., "Fatty acid binding protein 7 regulates phagocytosis and cytokine production in Kupffer cells during liver injury", Am. J. Pathol, 184, pp.2505~2515 (2014)
- Zhou, L., "Cidea promotes hepatic steatosis by sensing dietary fatty acids", Hepatology, 56, pp.95~107 (2012)
- Swanzey, E., "Mouse genetic reference populations : cellular platforms for integrative systems genetics", Trends Genet, 37, pp.251~265 (2021)
- Lonsdale, J., "The genotype-tissue expression(GTEx)project", Nat. Genet, 45, pp.580~585 (2013)
- Verstraete, K., "Acetyl-CoA is produced by the citrate synthase homology module of ATP-citrate lyase", Nat. Struct. Mol. Biol, 28, pp.636~638 (2021)
- Tsai, M. -T., "Identification of potential plasma biomarkers for nonalcoholic fatty liver disease by integrating transcriptomics and proteomics in laying hens", J. Nutr, 147, pp.293~303 (2017)
- Hui, S. T., "The genetic architecture of NAFLD among inbred strains of mice", eLife, 4, pp.e05607~ (2015)
- Sztolsztener, K., "Arachidonic acid as an early indicator of inflammation during non-alcoholic fatty liver disease development", Biomolecules, 10, pp.1133~ (2020)
- Rensen, S. S., "Activation of the complement system in human nonalcoholic fatty liver disease", Hepatology(Baltimore, Md.), 50, pp.1809~1817 (2009)
- Pettinelli, P., "Altered hepatic genes related to retinol metabolism and plasma retinol in patients with non-alcoholic fatty liver disease", PLoS ONE, 13, pp.e0205747~ (2018)
- Schep, A. N., "chromVAR: inferring transcription-factor-associated accessibility from single-cell epigenomic data", Nat. Methods, 14, pp.975~978 (2017)
- Zhan, Q., "Function annotation of hepatic retinoid x receptor α based on genome-wide DNA binding and transcriptome profiling", PLoS ONE, 7, pp.e50013~ (2012)
- Agius, L., "The protective role of the carbohydrate response element binding protein in the liver : the metabolite perspective", Front. Endocrinol, 11, pp.594041~ (2020)
- Moslehi, A., "Role of SREBPs in liver diseases : a mini-review", J. Clin. Transl. Hepatol, 6, pp.332~338 (2018)
- Steensels, S., "Transcriptional regulation in non-alcoholic fatty liver disease", Metabolites, 10, pp.283~ (2020)
- Jiang, S., "TRIM24 suppresses development of spontaneous hepatic lipid accumulation and hepatocellular carcinoma in mice", J. Hepatol, 62, pp.371~379 (2015)
- Ignat, M., "Development of a methodology for in vivo follow-up of hepatocellular carcinoma in hepatocyte specific Trim24-null mice treated with myoinositol trispyrophosphate", J. Exp. Clin. Cancer Res, 35, pp.1~11 (2016)
- Cha, J. Y., "The liver X receptor(LXR)and hepatic lipogenesis : the carbohydrate-response element-binding protein is a target gene of LXR", J. Biol. Chem, 282, pp.743~751 (2007)
- Meng, F., "FGF21 ameliorates hepatic fibrosis by multiple mechanisms", Mol. Biol. Rep, 48, pp.7153~7163 (2021)
- Montagner, A., "Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD", Gut, 65, pp.1202~1214 (2016)
- Su, Q., "Single-cell RNA transcriptome landscape of hepatocytes and nonparenchymal cells in healthy and NAFLD mouse liver", iScience, 24, pp.103233~ (2021)
- Li, J., "VSIG4 inhibits proinflammatory macrophage activation by reprogramming mitochondrial pyruvate metabolism", Cardiol. Res, 8, pp.1~14 (2017)
- Han, X., "Mapping the mouse cell atlas by microwell-seq", Cell, 172, pp.1091~1107 (2018)
- Fei, L., "Systematic identification of cell fate regulatory programs using a single-cell atlas of mouse development", Nat. Genet, 54, pp.1051~1061 (2022)
- Balsa, E., "Defective NADPH production in mitochondrial disease complex I causes inflammation and cell death", Nat. Commun, 11, pp.1~12 (2020)
- 진효선, "Mitochondrial Control of Innate Immunity and Inflammation", Immune Network, 17(2), pp.77~88 (2017), 대한면역학회[DOI]
- Akiel, M., "IGFBP7 Deletion Promotes Hepatocellular CarcinomaPromotion of HCC in Igfbp7ko Mice", Cancer Res, 77, pp.4014~4025 (2017)
- Li, H., "Crosstalk between liver macrophages and surrounding cells in nonalcoholic steatohepatitis", Front. Immunol, 11, pp.1169~ (2020)
- Hou, J., "TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis", J. Clin. Investig, 131, pp.e135197~ (2021)
- Hendrikx, T., "Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH", J. Hepatol, 77, pp.1373~1385 (2022)
- Basaranoglu, M., "Carbohydrate intake and nonalcoholic fatty liver disease : fructose as a weapon of mass destruction", Hepatobiliary Surg. Nutr, 4, pp.109~116 (2015)
- Pompili, S., "Long-term abuse of a high-carbohydrate diet is as harmful as a high-fat diet for development and progression of liver injury in a mouse model of NAFLD", NASH, 2020, pp.75, 110782~
- Chiu, S., "Dietary carbohydrates and fatty liver disease : de novo lipogenesis", Curr. Opin. Clin. Nutr. Metabolic Care, 21, pp.277~282 (2018)
- Shakerian, E., "Effect of high concentrations of fructose on the expression of TGF-β and α-SMA genes in human hepatic stellate cells", J. Cellular Mol. Biol, 11, pp.e110136~ (2020)
- Liu, X., "Mechanisms of liver injury in high fat sugar diet fed mice that lack hepatocyte X-box binding protein 1", PLoS ONE, 17, pp.e0261789~ (2022)
- Sugimoto, R., "High glucose stimulates hepatic stellate cells to proliferate and to produce collagen through free radical production and activation of mitogenactivated protein kinase", Liver Int, 25, pp.1018~1026 (2005)
- Zhang, C. Y., "Liver fibrosis and hepatic stellate cells : etiology, pathological hallmarks and therapeutic targets", World J. Gastroenterol, 22, pp.10512~10522 (2016)
- Piras, I. S., "Palmitate and fructose interact to induce human hepatocytes to produce pro-fibrotic transcriptional responses in hepatic stellate cells exposed to conditioned media", Cellular Physiol. Biochem, 54, pp.1068~1082 (2020)
- Apostolopoulos, J., "Ly6d-L, a cell surface ligand for mouse Ly6d", Immunity, 12, pp.223~232 (2000)
- Barros-Silva, J. D., "Single-cell analysis identifies LY6D as a marker linking castration-resistant prostate luminal cells to prostate progenitors and cancer", Cell Rep, 25, pp.3504~3518 (2018)
- Guillén, N., "Microarray analysis of hepatic gene expression identifies new genes involved in steatotic liver", Physiol. Genomics, 37, pp.187~198 (2009)
- Owada, Y., "Novel non-alcoholic steatohepatitis model with histopathological and insulin-resistant features", Pathol. Int, 68, pp.12~22 (2018)
- Sutti, S., "Adaptive immunity : an emerging player in the progression of NAFLD", Nat. Rev. Gastroenterol Hepatol, 17, pp.81~92 (2020)
- Sands, M. S., "Adeno-Associated Virus", pp.141~157 (2012), Springer