Noncoding RNAs as additional mediators of epigenetic regulation in nonalcoholic fatty liver disease

Table 1 Selected microRNAs shown to be highly involved in the pathogenesis of nonalcoholic fatty liver disease

miRNA	Circulation level	Tissue expression	Main functional and pathophysiological impacts	Ref.
miR-21	↑	↑	Promotes lipogenesis	[38-40,42,44]
			Involved in NASH, fibrosis, and HCC
			Targets several metabolic and inflammatory signaling pathways related to the pathogenesis of NAFLD
miR-29a	↑	↓	Highly connected with the diagnostic relevance of NAFLD, NASH, and HCC	[31,53, 52,58]
			Modulates oxidative stress and inflammation in the context of NAFLD
miR-33a/b	↑	↑	Involved in lipid metabolism, glucose homeostasis and hepatic lipogenesis	[61-63,65]
			Associated with steatosis and inflammation in patients with NAFLD/NASH
miR-34a	↑	↑	Regulates lipoprotein metabolism and promotes liver steatosis	[72,73,75]
			Involved in NAFLD/NASH
			Correlates with the severity of hepatic inflammatory activity
			Can serve as a biomarker to distinguish NAFLD from NASH patients
miR-122	↑	↓	Modulates several genes linked to chronic hepatic pathology and lipid metabolism	[74,82-84]
			Promotes hepatic steatosis
			Serum miR-122 correlates positively with markers of NAFLD severity as well as with NASH
miR-155	↑	↑	Regulates key cellular events in NAFLD/NASH	[96,97]
			Promotes insulin resistance
miR-192	↑	↓	Significantly elevated in NAFLD patients and positively associated with hepatic inflammatory activity score and disease progression	[32,80,100]
			Increased in serum from NASH patients compared with steatosis
			Could be a potential biomarker of NAFLD and NASH
miR-375	↑	↑	Involved in the pathogenesis of NAFLD/NASH/fibrosis	[80,102]
			Key regulator of glucose homeostasis and insulin secretion

HCC: Hepatocellular carcinoma; miRNAs: MicroRNAs; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis.

Table 2 Relevant dysregulated long noncoding RNAs associated with alterations in liver metabolism and nonalcoholic fatty liver disease

lncRNA	Expression	Main functional and pathophysiological effects	Ref.
MALAT1	↑	Promotes cell proliferation, migration, and invasion in several different human cancers including HCC	[119-122]
		Promotes hepatic steatosis and insulin resistance
		Hepatic MALAT1 levels are higher in NASH patients with fibrosis
		Promotes NAFLD progression and increase with the severity of the disease
NEAT1	↑	Promotes adipogenesis, lipogenesis, and lipid absorption	[124,126,127]
		Modulates fibrosis and inflammatory responses
		Silencing NEAT1 alleviated fibrosis and inflammatory in a NAFLD cellular model
MEG3	↓	Involved in lipid metabolism and glucose homeostasis	[131-134]
		Correlates with steatosis and inflammation (NASH) in patients with NAFLD
HULC	↑	Promotes HCC growth and metastasis	[135,136]
		Promotes NAFLD development
		Metformin decreases HULC expression
HOTAIR	↑	Activates lipid accumulation in hepatocytes and promotes hepatic steatosis development	[139-141]
		Expression profile is significantly increased in oleic acid-induced steatosis and during the development of HFD-induced NAFLD
		Accelerates liver fibrosis and carcinogenesis
FLRL2	↓	Decreases endoplasmic reticulum stress and liver inflammation	[143]
		Alleviates NAFLD and steatosis in mouse model

FLR2: Fatty liver-related lncRNA 2; H19: H19 imprinted maternally expressed transcript; HCC: Hepatocellular carcinoma; HFD: High-fat diet; HOTAIR: HOX transcript antisense RNA; MALAT1: Metastasis-associated lung adenocarcinoma transcript 1; lncRNAs: Long noncoding RNAs; MEG3: Maternally expressed 3; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; NEAT1: Nuclear paraspeckle assembly transcript 1; HULC: Hepatocellular carcinoma upregulated long noncoding RNA.

Table 3 Relevant dysregulated circular RNAs associated with alterations in liver metabolism and nonalcoholic fatty liver disease

circRNA	Expression level	Main functional and pathophysiological effects	Ref.
circRNA_0046367	↑	Inhibits hepatic steatosis by preventing hepatotoxicity of lipid peroxidation	[148]
circRNA_0046366	↑	Inhibits hepatic steatosis through miR-34a/PPARα	[149]
circRNA_021412	↑	Associated with hepatic steatosis	[150]
circScd1	↓	Affects steatosis on NAFLD via JAK2/STAT5 signaling pathways	[151]
hsa_circ_0048179	↓	Attenuates free fatty acid-induceded steatosis by sponging of miR-188-3p in vitro	[152]
mmu_circRNA_29981	↑	Regulatory role in NASH mousee model	[153]
Circ_0057558	↑	Involved in lipogenesis	[156]
		Promotes nonalcoholic fatty liver disease by sponging miR-206
SCAR	↓	Correlates with steatosis-to-NASH progression	[157]
		In vivo, targeting circRNA SCAR alleviates HFD-induced cirrhosis and insulin resistance

circRNAs: Circular RNAs; HCC: Hepatocellular carcinoma; HFD: High-fat diet; JAK2: Janus Kinase 2; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; PPARα: Peroxisome proliferator-activated receptor α; STAT5: Signal transducer and activator of transcription 5.