Emerging novel targets for nonalcoholic fatty liver disease treatment: Evidence from recent basic studies

Table 2 Novel extrahepatic targets explored by recent basic study

Molecular target	Potential agent	Classification	Function	Effect	Ref.
AMPK	UO-Zn	Small molecule	Improve lipid metabolism	-Lipid accumulation in liver and circulation	[106]
BDK	BT2	Inhibitor	Regulating BCAA metabolism	-Hepatic steatosis	[107,108]
				-Liver inflammation
				-Liver fibrosis
HIF-2α (gut)	PT2385	Inhibitor	Decrease intestine-derived ceramide	-Hepatic steatosis	[112]
				-Liver injury
MYC (gut)	10058-F4	Inhibitor	Decrease intestine-derived ceramide	-Hepatic steatosis	[114]
				-Liver injury
				-Liver fibrosis
5-HT(gut)/HTR2A	Sarpogrelate	Antagonist	Inhibit gut-5-HT-liver Htr2α pathway	-Hepatic steatosis	[116]
PPARα (gut)	GW6471	Antagonist	Inhibit fatty acid absorption by intestine	-Hepatic steatosis	[117]
				-Liver inflammation
				-Liver fibrosis
MGAT2	BMS-963272	Inhibitor	Regulating fat absorption and liver TG synthesis	-Liver inflammation	[119]
				-Liver fibrosis
ISM1 (AT)	Recombinant Ism1	Recombinant protein	Suppress lipogenesis in liver	-Hepatic steatosis	[122]
				+Glucose tolerance
Sparcl1 (AT)	Anti-Sparcl1 antibody	Neutralizing antibody	Decrease CCL2 expression in liver	-Liver inflammation	[123]
				-Liver fibrosis
Gremlin 1 (AT)	Anti-Gremlin 1 antibody	Neutralizing antibody	Increase insulin sensitivity	-Insulin resistance	[124]
NRG4	hNRG4-Fc	Recombinant protein	Restrain the tumor-prone liver immune microenvironment	-NASH-associated HCC	[125]
SWELL1/LRRC8a (AT)	SN-401	Small molecule	Enhance insulin sensitivity and secretion	+Insulin sensitivity	[128]
				-Hepatic steatosis
				-Hepatocyte damage

AT: Adipose tissue; -: Inhibit; +: Stimulate; AMPK: AMP-activated protein kinase; BDK: Branched chain ketoacid dehydrogenase kinase; BCAA: Branched-chain amino acids; HIF-2α: Hypoxia-inducible factor 2α; MYC: Myelocytomatosis oncogene; 5-HT: 5-hydroxytryptamine; PPAR: Peroxisome proliferator-activated receptor; MGAT2: Monoacylglycerol acyltransferase 2; TG: Triglyceride; ISM1: Isthmin-1; Sparcl1: Secreted protein acidic and rich in cysteine-like protein 1; CCL2: C-C motif chemokine ligand 2; NRG4: Neuregulin 4; hNRG4-Fc: Human NRG4 and the Fc domain of immunoglobulin G 1; NASH: Nonalcoholic steatohepatitis; HCC: Hepatocellular carcinoma; UO: Ulvan oligosaccharide; BT2: 3,6-dichlorobrenzo(b)thiophene-2-carboxylic acid.