Name	Non-alcoholic fatty liver disease
ICD	ICD-11: DB92

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[1]
Response Summary	In nonalcoholic fatty liver disease, Ythdc2 could bind to mRNA of lipogenic genes, including sterol regulatory element-binding protein 1c, fatty acid synthase, stearoyl-CoA desaturase 1, and Acetyl-CoA carboxylase 1 (ACC1/ACACA), to decrease their mRNA stability and inhibit gene expression.
Responsed Disease	Non-alcoholic fatty liver disease [ICD-11: DB92]
Target Regulator	YTH domain-containing protein 2 (YTHDC2)		READER	Regulator Info
Target Regulation	Down regulation
Pathway Response	RNA degradation			hsa03018
Cell Process	RNA stability
In-vivo Model	All mice were housed at 21℃ ± 1℃ with a humidity of 55% ± 10% and a 12-hour light/dark cycle. The high-fat diets (HFDs), containing 60% kcal from fat, 20% kcal from carbohydrate, and 20% kcal from protein.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[2]
Response Summary	Targeting METTL3/14 in vitro increases protein level of ATP-citrate synthase (ACLY) and SCD1 as well as triglyceride and cholesterol production and accumulation of lipid droplets. These findings demonstrate a new NAFLD mouse model that provides a study platform for DM2-related NAFLD and reveals a unique epitranscriptional regulating mechanism for lipid metabolism via m6A-modified protein expression of ACLY and SCD1.
Responsed Disease	Non-alcoholic fatty liver disease [ICD-11: DB92]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Up regulation
Pathway Response	Glycerolipid metabolism			hsa00561
Cell Process	Lipid metabolism
In-vitro Model	LM3	Malignant neoplasms	Mus musculus	CVCL_D269
	MHCC97-H	Adult hepatocellular carcinoma	Homo sapiens	CVCL_4972
In-vivo Model	Mice with a Tmem30a deletion specifically in pancreatic beta cells were generated as previously described. Mice developed with NAFLD were named for Tmem30a-associated NAFLD (TAN) mice. The littermate mice with genotypes of Tmem30aloxP/loxP were used as controls.

In total 2 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[3]
Response Summary	The upregulation of METTL3 and YTHDF1 induced by lipotoxicity contributes to the elevated expression level of Beclin-1 associated RUN domain containing protein (RUBCN/Rubicon) in an m6A-dependent manner, which inhibits the fusion of autophagosomes and lysosomes and further suppresses the clearance of LDs via lysosomes in nonalcoholic fatty liver disease.
Responsed Disease	Non-alcoholic fatty liver disease [ICD-11: DB92]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Up regulation
Pathway Response	Autophagy			hsa04140
Cell Process	Cell autophagy
In-vitro Model	AML12	Normal	Mus musculus	CVCL_0140
	Hepa 1-6	Hepatocellular carcinoma of the mouse	Mus musculus	CVCL_0327
	Hep-G2	Hepatoblastoma	Homo sapiens	CVCL_0027
In-vivo Model	All mice were housed in specific pathogen-free conditions in the animal facility with constant temperature and humidity under a 12-h light/12-h dark cycle, with free access to water and food. After a week of adaptation, they were then divided into two groups randomly and fed with a HFD (60 kcal% fat, D12492, Research Diets) or standard normal chow diet (CD) for 16 weeks, respectively.
Experiment 2 Reporting the m6A-centered Disease Response by This Target Gene				[3]
Response Summary	The upregulation of METTL3 and YTHDF1 induced by lipotoxicity contributes to the elevated expression level of Beclin-1 associated RUN domain containing protein (RUBCN/Rubicon) in an m6A-dependent manner, which inhibits the fusion of autophagosomes and lysosomes and further suppresses the clearance of LDs via lysosomes in nonalcoholic fatty liver disease.
Responsed Disease	Non-alcoholic fatty liver disease [ICD-11: DB92]
Target Regulator	YTH domain-containing family protein 1 (YTHDF1)		READER	Regulator Info
Target Regulation	Up regulation
Pathway Response	Autophagy			hsa04140
Cell Process	Cell autophagy
In-vitro Model	AML12	Normal	Mus musculus	CVCL_0140
	Hepa 1-6	Hepatocellular carcinoma of the mouse	Mus musculus	CVCL_0327
	Hep-G2	Hepatoblastoma	Homo sapiens	CVCL_0027
In-vivo Model	All mice were housed in specific pathogen-free conditions in the animal facility with constant temperature and humidity under a 12-h light/12-h dark cycle, with free access to water and food. After a week of adaptation, they were then divided into two groups randomly and fed with a HFD (60 kcal% fat, D12492, Research Diets) or standard normal chow diet (CD) for 16 weeks, respectively.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[4]
Response Summary	Liver-specific Mettl3 knockout mice exhibited global decrease in m6A on polyadenylated RNAs and pathologic features associated with nonalcoholic fatty liver disease. Studies in the M3LKO model indicated that METTL3 exhibits pleotropic function to maintain liver homeostasis by deregulating m6A profile and expression of the liver transcriptome. A significant decrease in total Brain and muscle ARNT-like 1 (Bmal1/ARNTL) and Clock mRNAs but an increase in their nuclear levels were observed in M3LKO livers, suggesting impaired nuclear export.
Responsed Disease	Non-alcoholic fatty liver disease [ICD-11: DB92]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Up regulation
In-vivo Model	M3LKO (Mettl3fl/fl; Alb-Cre) mice were generated by crossing Mettl3fl/fl mice (provided by Dr. Jacob Hanna) with albumin-Cre mice (Jackson Laboratories, Bar Harbor, ME), and genotypes were confirmed by tail-DNA PCR using primers as previously described.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[5]
Response Summary	FTO increased the lipid accumulation in hepatocytes by increasing nuclear translocation of SREBP1c and SREBP1c maturation, thus improving the transcriptional activity of LD-associated protein Cell death activator CIDE-3 (CIDEC).The studies provide new mechanistic insight into nonalcoholic fatty liver disease (NAFLD) mediated by FTO.
Responsed Disease	Non-alcoholic fatty liver disease [ICD-11: DB92]
Target Regulator	Fat mass and obesity-associated protein (FTO)		ERASER	Regulator Info
Target Regulation	Up regulation
Cell Process	Lipogenesis
In-vitro Model	HEK293T	Normal	Homo sapiens	CVCL_0063
	Hep-G2	Hepatoblastoma	Homo sapiens	CVCL_0027
In-vivo Model	After being fed with high-fat diet for 4 weeks, mice were given twice vena caudalis injection of control siRNA or Cidec siRNA (50 ug/mouse) mixed with liposome. Liposomes were prepared as described elsewhere.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[4]
Response Summary	Liver-specific Mettl3 knockout mice exhibited global decrease in m6A on polyadenylated RNAs and pathologic features associated with nonalcoholic fatty liver disease. Studies in the M3LKO model indicated that METTL3 exhibits pleotropic function to maintain liver homeostasis by deregulating m6A profile and expression of the liver transcriptome. A significant decrease in total Bmal1 and Circadian locomoter output cycles protein kaput (CLOCK) mRNAs but an increase in their nuclear levels were observed in M3LKO livers, suggesting impaired nuclear export.
Responsed Disease	Non-alcoholic fatty liver disease [ICD-11: DB92]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Up regulation
In-vivo Model	M3LKO (Mettl3fl/fl; Alb-Cre) mice were generated by crossing Mettl3fl/fl mice (provided by Dr. Jacob Hanna) with albumin-Cre mice (Jackson Laboratories, Bar Harbor, ME), and genotypes were confirmed by tail-DNA PCR using primers as previously described.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[6]
Response Summary	The contribution of METTL3-mediated m6A modification of DNA damage-inducible transcript 4 protein (DDIT4) mRNA to macrophage metabolic reprogramming in non-alcoholic fatty liver disease and obesity. In METTL3-deficient macrophages, there is a significant downregulation of mammalian target of rapamycin (mTOR) and nuclear factor Kappa-B (NF-Kappa-B) pathway activity in response to cellular stress and cytokine stimulation, which can be restored by knockdown of DDIT4.
Responsed Disease	Non-alcoholic fatty liver disease [ICD-11: DB92]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Down regulation
Pathway Response	mTOR signaling pathway			hsa04150
	HIF-1 signaling pathway			hsa04066
In-vivo Model	The 8-10 weeks old mice were fed either a high fat diet or HF-CDAA , ad lib for 6-12 weeks. Chow diet was used as control for HFD.The mouse liver was perfused with PBS through portal vein, and liver tissue was cut into small pieces by a scissor. The single cell was made using syringe plunger to mull the tissue, and passed through a 40 uM cell strainer.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[7]
Response Summary	Mechanistically, METTL3 directly binds to the promoters of the Cd36 and Monocyte chemotactic and activating factor (CCL2) genes and recruits HDAC1/2 to induce deacetylation of H3K9 and H3K27 in their promoters, thus suppressing Cd36 and Ccl2 transcription. METTL3 negatively regulates hepatic Cd36 and Ccl2 gene transcription via a histone modification pathway for protection against Nonalcoholic steatohepatitis(NASH) progression.
Responsed Disease	Nonalcoholic steatohepatitis [ICD-11: DB92.1]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Down regulation
In-vitro Model	HEK293T	Normal	Homo sapiens	CVCL_0063
In-vivo Model	Mettl3flox/flox and Mettl3-HKO mice were fasted overnight and then injected intraperitoneally with 20 uM BODIPY FL C16 in 200 ul saline for 20 min.

In total 2 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[8]
Response Summary	Nuclear factor NF-kappa-B p105 subunit (NF-Kappa-B/NFKB1) acts as transcription factor to transactivate METTL3/METTL14 genes upon LPS challenge, leading to global RNA m6A hypermethylation. m6A modification in TGF-beta1 upregulation, which helps to shed light on the molecular mechanism of nonalcoholic steatohepatitis(NASH) progression.
Responsed Disease	Nonalcoholic steatohepatitis [ICD-11: DB92.1]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Up regulation
In-vitro Model	KCs (Mouse Kupffer cells (BeNa Culture Collection, Beijing, China; BNCC340733))
In-vivo Model	At 8 weeks of age, METTL14 cKO and WT mice were challenged with LPS (Sigma-Aldrich, St. Louis, MO; L2880, single intraperitoneal injection at 5 mg/kg, n = 3) or CCl4 (10%, Macklin, Shanghai, China; C805332, intraperitoneal injection at 5 mL/kg diluted with corn oil, twice per week for 4 weeks, n = 3). The corresponding control groups were treated with single intraperitoneal injection of saline (n = 3) or intraperitoneal injection of corn oil twice per week for 4 weeks (n = 3), respectively. Two hours after LPS injection and 4 weeks after CCl4 treatment, METTL14 cKO and WT mice were etherized and the primary KCs were isolated from liver according to a previously published method.
Experiment 2 Reporting the m6A-centered Disease Response by This Target Gene				[8]
Response Summary	Nuclear factor NF-kappa-B p105 subunit (NF-Kappa-B/NFKB1) acts as transcription factor to transactivate METTL3/METTL14 genes upon LPS challenge, leading to global RNA m6A hypermethylation. m6A modification in TGF-beta1 upregulation, which helps to shed light on the molecular mechanism of nonalcoholic steatohepatitis(NASH) progression.
Responsed Disease	Nonalcoholic steatohepatitis [ICD-11: DB92.1]
Target Regulator	Methyltransferase-like 14 (METTL14)		WRITER	Regulator Info
Target Regulation	Up regulation
In-vitro Model	KCs (Mouse Kupffer cells (BeNa Culture Collection, Beijing, China; BNCC340733))
In-vivo Model	At 8 weeks of age, METTL14 cKO and WT mice were challenged with LPS (Sigma-Aldrich, St. Louis, MO; L2880, single intraperitoneal injection at 5 mg/kg, n = 3) or CCl4 (10%, Macklin, Shanghai, China; C805332, intraperitoneal injection at 5 mL/kg diluted with corn oil, twice per week for 4 weeks, n = 3). The corresponding control groups were treated with single intraperitoneal injection of saline (n = 3) or intraperitoneal injection of corn oil twice per week for 4 weeks (n = 3), respectively. Two hours after LPS injection and 4 weeks after CCl4 treatment, METTL14 cKO and WT mice were etherized and the primary KCs were isolated from liver according to a previously published method.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[7]
Response Summary	Mechanistically, METTL3 directly binds to the promoters of the Platelet glycoprotein 4 (CD36) genes and recruits HDAC1/2 to induce deacetylation of H3K9 and H3K27 in their promoters, thus suppressing Cd36 and Ccl2 transcription. METTL3 negatively regulates hepatic Cd36 and Ccl2 gene transcription via a histone modification pathway for protection against Nonalcoholic steatohepatitis(NASH) progression.
Responsed Disease	Nonalcoholic steatohepatitis [ICD-11: DB92.1]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Down regulation
In-vitro Model	HEK293T	Normal	Homo sapiens	CVCL_0063
In-vivo Model	Mettl3flox/flox and Mettl3-HKO mice were fasted overnight and then injected intraperitoneally with 20 uM BODIPY FL C16 in 200 ul saline for 20 min.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[6]
Response Summary	The contribution of METTL3-mediated m6A modification of Ddit4 mRNA to macrophage metabolic reprogramming in non-alcoholic fatty liver disease and obesity. In METTL3-deficient macrophages, there is a significant downregulation of Serine/threonine-protein kinase mTOR (MTOR) and nuclear factor Kappa-B (NF-Kappa-B) pathway activity in response to cellular stress and cytokine stimulation, which can be restored by knockdown of DDIT4.
Responsed Disease	Non-alcoholic fatty liver disease [ICD-11: DB92]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Up regulation
Pathway Response	mTOR signaling pathway			hsa04150
	HIF-1 signaling pathway			hsa04066
In-vivo Model	The 8-10 weeks old mice were fed either a high fat diet or HF-CDAA , ad lib for 6-12 weeks. Chow diet was used as control for HFD.The mouse liver was perfused with PBS through portal vein, and liver tissue was cut into small pieces by a scissor. The single cell was made using syringe plunger to mull the tissue, and passed through a 40 uM cell strainer.

In total 2 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[1]
Response Summary	In nonalcoholic fatty liver disease, Ythdc2 could bind to mRNA of lipogenic genes, including sterol regulatory element-binding protein 1c, fatty acid synthase, Stearoyl-CoA desaturase (SCD), and acetyl-CoA carboxylase 1, to decrease their mRNA stability and inhibit gene expression.
Responsed Disease	Non-alcoholic fatty liver disease [ICD-11: DB92]
Target Regulator	YTH domain-containing protein 2 (YTHDC2)		READER	Regulator Info
Target Regulation	Down regulation
Pathway Response	RNA degradation			hsa03018
Cell Process	RNA stability
In-vivo Model	All mice were housed at 21℃ ± 1℃ with a humidity of 55% ± 10% and a 12-hour light/dark cycle. The high-fat diets (HFDs), containing 60% kcal from fat, 20% kcal from carbohydrate, and 20% kcal from protein.
Experiment 2 Reporting the m6A-centered Disease Response by This Target Gene				[2]
Response Summary	Targeting METTL3/14 in vitro increases protein level of ACLY and Stearoyl-CoA desaturase (SCD) as well as triglyceride and cholesterol production and accumulation of lipid droplets. These findings demonstrate a new NAFLD mouse model that provides a study platform for DM2-related NAFLD and reveals a unique epitranscriptional regulating mechanism for lipid metabolism via m6A-modified protein expression of ACLY and SCD1.
Responsed Disease	Non-alcoholic fatty liver disease [ICD-11: DB92]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Up regulation
Pathway Response	Glycerolipid metabolism			hsa00561
Cell Process	Lipid metabolism
In-vitro Model	LM3	Malignant neoplasms	Mus musculus	CVCL_D269
	MHCC97-H	Adult hepatocellular carcinoma	Homo sapiens	CVCL_4972
In-vivo Model	Mice with a Tmem30a deletion specifically in pancreatic beta cells were generated as previously described. Mice developed with NAFLD were named for Tmem30a-associated NAFLD (TAN) mice. The littermate mice with genotypes of Tmem30aloxP/loxP were used as controls.

In total 2 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[5]
Response Summary	FTO increased the lipid accumulation in hepatocytes by increasing nuclear translocation of Sterol regulatory element-binding protein 1 (SREBF1) and SREBP1c maturation, thus improving the transcriptional activity of LD-associated protein CIDEC.The studies provide new mechanistic insight into nonalcoholic fatty liver disease (NAFLD) mediated by FTO.
Responsed Disease	Non-alcoholic fatty liver disease [ICD-11: DB92]
Target Regulator	Fat mass and obesity-associated protein (FTO)		ERASER	Regulator Info
Target Regulation	Up regulation
Cell Process	Lipogenesis
In-vitro Model	HEK293T	Normal	Homo sapiens	CVCL_0063
	Hep-G2	Hepatoblastoma	Homo sapiens	CVCL_0027
In-vivo Model	After being fed with high-fat diet for 4 weeks, mice were given twice vena caudalis injection of control siRNA or Cidec siRNA (50 ug/mouse) mixed with liposome. Liposomes were prepared as described elsewhere.
Experiment 2 Reporting the m6A-centered Disease Response by This Target Gene				[1]
Response Summary	In nonalcoholic fatty liver disease, Ythdc2 could bind to mRNA of lipogenic genes, including Sterol regulatory element-binding protein 1 (SREBF1), fatty acid synthase, stearoyl-CoA desaturase 1, and acetyl-CoA carboxylase 1, to decrease their mRNA stability and inhibit gene expression.
Responsed Disease	Non-alcoholic fatty liver disease [ICD-11: DB92]
Target Regulator	YTH domain-containing protein 2 (YTHDC2)		READER	Regulator Info
Target Regulation	Down regulation
Pathway Response	RNA degradation			hsa03018
Cell Process	RNA stability
In-vivo Model	All mice were housed at 21℃ ± 1℃ with a humidity of 55% ± 10% and a 12-hour light/dark cycle. The high-fat diets (HFDs), containing 60% kcal from fat, 20% kcal from carbohydrate, and 20% kcal from protein.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[1]
Response Summary	In nonalcoholic fatty liver disease, Ythdc2 could bind to mRNA of lipogenic genes, including sterol regulatory element-binding protein 1c, Tumor necrosis factor receptor superfamily member 6 (FAS), stearoyl-CoA desaturase 1, and acetyl-CoA carboxylase 1, to decrease their mRNA stability and inhibit gene expression.
Responsed Disease	Non-alcoholic fatty liver disease [ICD-11: DB92]
Target Regulator	YTH domain-containing protein 2 (YTHDC2)		READER	Regulator Info
Target Regulation	Down regulation
Pathway Response	RNA degradation			hsa03018
Cell Process	RNA stability
In-vivo Model	All mice were housed at 21℃ ± 1℃ with a humidity of 55% ± 10% and a 12-hour light/dark cycle. The high-fat diets (HFDs), containing 60% kcal from fat, 20% kcal from carbohydrate, and 20% kcal from protein.

Ref 1	N(6) -Methyladenosine Reader Protein YT521-B Homology Domain-Containing 2 Suppresses Liver Steatosis by Regulation of mRNA Stability of Lipogenic Genes. Hepatology. 2021 Jan;73(1):91-103. doi: 10.1002/hep.31220. Epub 2020 Oct 25.
Ref 2	Dysregulated m6A modification promotes lipogenesis and development of non-alcoholic fatty liver disease and hepatocellular carcinoma. Mol Ther. 2022 Jun 1;30(6):2342-2353. doi: 10.1016/j.ymthe.2022.02.021. Epub 2022 Feb 19.
Ref 3	METTL3-m(6)A-Rubicon axis inhibits autophagy in nonalcoholic fatty liver disease. Mol Ther. 2022 Feb 2;30(2):932-946. doi: 10.1016/j.ymthe.2021.09.016. Epub 2021 Sep 20.
Ref 4	METTL3 Regulates Liver Homeostasis, Hepatocyte Ploidy, and Circadian Rhythm-Controlled Gene Expression in Mice. Am J Pathol. 2022 Jan;192(1):56-71. doi: 10.1016/j.ajpath.2021.09.005. Epub 2021 Sep 29.
Ref 5	FTO promotes SREBP1c maturation and enhances CIDEC transcription during lipid accumulation in HepG2 cells. Biochim Biophys Acta Mol Cell Biol Lipids. 2018 May;1863(5):538-548. doi: 10.1016/j.bbalip.2018.02.003. Epub 2018 Feb 25.
Ref 6	m(6)A mRNA methylation-directed myeloid cell activation controls progression of NAFLD and obesity. Cell Rep. 2021 Nov 9;37(6):109968. doi: 10.1016/j.celrep.2021.109968.
Ref 7	The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression. Nat Commun. 2021 Dec 10;12(1):7213. doi: 10.1038/s41467-021-27539-3.
Ref 8	METTL3/METTL14 Transactivation and m(6)A-Dependent TGF-Beta1 Translation in Activated Kupffer Cells. Cell Mol Gastroenterol Hepatol. 2021;12(3):839-856. doi: 10.1016/j.jcmgh.2021.05.007. Epub 2021 May 13.