The roles of different microRNAs in the regulation of cholesterol in viral hepatitis

Abstract

Cholesterol plays a significant role in stabilizing lipid or membrane rafts, which are specific cellular membrane structures. Cholesterol is involved in numerous cellular processes, including regulating virus entry into the host cell. Multiple viruses have been shown to rely on cholesterol for virus entry and/or morphogenesis. Research indicates that reprogramming of the host's lipid metabolism is associated with hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in the progression to severe liver disease for viruses that cause chronic hepatitis. Moreover, knowing the precise mode of viral interaction with target cells sheds light on viral pathogenesis and aids in the development of vaccines and therapeutic targets. As a result, the area of cholesterol-lowering therapy is quickly evolving and has many novel antiviral targets and medications. It has been shown that microRNAs (miRNAs) either directly or indirectly target the viral genome, preventing viral replication. Moreover, miRNAs have recently been shown to be strong post-transcriptional regulators of the genes involved in lipid metabolism, particularly those involved in cholesterol homeostasis. As important regulators of lipid homeostasis in several viral infections, miRNAs have recently come to light. In addition, multiple studies demonstrated that during viral infection, miRNAs modulate several enzymes in the mevalonate/cholesterol pathway. As cholesterol metabolism is essential to the life cycle of viral hepatitis and other viruses, a sophisticated understanding of miRNA regulation may contribute to the development of a novel anti-HCV treatment. The mechanisms underlying the effectiveness of miRNAs as cholesterol regulators against viral hepatitis are explored in this review. Video Abstract.

Keywords: Cholesterol; Viral hepatitis; Viral infections; microRNAs.

Fig. 1

Biogenesis of miRNAs and Cholesterol Control. In a nutshell, miRNAs are first transcribed by RNA polymerase II (RNAP II), which then produces an initial transcript known as produced precursor miRNAs (pri-miRNA) [22, 23]. Following transcription, the common hairpin-loop secondary structure seen in pri-miRNAs is recognized and cleaved by the microprocessor complex (created by DGCR8 and Drosha). To create a double-stranded RNA, pre-miRNAs are transferred to the cytoplasm and then digested by the Dicer nuclease. The RNA-induced silencing complex (RISC), which utilizes the mature miRNA sequence to perform its regulatory role, is chosen through Ago2 [–26]. Each miRNA may bind to a number of mRNAs involved in the transport, storage, utilization, and/or excretion of cholesterol as well as in its production, absorption, efflux, and other processes

Fig. 2

Reverse cholesterol transport and miRNAs in cholesterol homeostasis. MiRNAs exert either positive/atheroprotective or negative/atherogenic effects in the liver by directing their attention to key mediators involved in cholesterol production. These miRNAs suppress the target genes’ mRNA and protein expression, as stated. A variety of miRNAs in the liver target ATP-binding cassette transporter A1 (ABCA1) to decrease cholesterol efflux to lipid-poor apolipoprotein A-I (apoA-I), which produces nascent HDL. Scavenger receptor B-I (SR-BI) specifically binds to HDL’s miRNA and cholesterol cargo upon return to the liver, where excess cholesterol is discharged into the bile. By preventing the production of the cholesterol transporters scavenger receptor BI (SR-BI) and LDLR, miRNAs aim to reduce the absorption of cholesterol into the liver. SR-BI, ABC11, and ATP8B1 transporter inhibition decrease the hepatic clearance and excretion of cholesterol [72, 73]

Fig. 3

miR-122’s role in HCV. Liver-specific miR-122 binds to two sites in the 5′UTR of the HCV genome and increases its translation and replication. Direct effect, caused by miR-122 targeting of the HCV RNA; indirect impact, caused by downregulation of HMOX1, which has been shown to prevent HCV replication. HCV RNA abundance significantly decreased as a result of miR-122. When miR-122 binds to the HCV genome’s 5′ UTR, ribosome interaction with the viral RNA is improved. Putative effectors of miR-122-mediated metabolic regulation have been proposed to include AMP-activated protein kinase (APK) and circadian metabolic regulators of the PPAR family [–89]