Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Mar 11:12:636897.
doi: 10.3389/fmicb.2021.636897. eCollection 2021.

Multifaceted Interaction Between Hepatitis B Virus Infection and Lipid Metabolism in Hepatocytes: A Potential Target of Antiviral Therapy for Chronic Hepatitis B

Jiaxuan Zhang  1 , Ning Ling  1 , Yu Lei  1 , Mingli Peng  1 , Peng Hu  1 , Min Chen  1
Affiliations
Review

Multifaceted Interaction Between Hepatitis B Virus Infection and Lipid Metabolism in Hepatocytes: A Potential Target of Antiviral Therapy for Chronic Hepatitis B

Jiaxuan Zhang et al. Front Microbiol. .

Abstract

Hepatitis B virus (HBV) is considered a "metabolic virus" and affects many hepatic metabolic pathways. However, how HBV affects lipid metabolism in hepatocytes remains uncertain yet. Accumulating clinical studies suggested that compared to non-HBV-infected controls, chronic HBV infection was associated with lower levels of serum total cholesterol and triglycerides and a lower prevalence of hepatic steatosis. In patients with chronic HBV infection, high ALT level, high body mass index, male gender, or old age was found to be positively correlated with hepatic steatosis. Furthermore, mechanisms of how HBV infection affected hepatic lipid metabolism had also been explored in a number of studies based on cell lines and mouse models. These results demonstrated that HBV replication or expression induced extensive and diverse changes in hepatic lipid metabolism, by not only activating expression of some critical lipogenesis and cholesterolgenesis-related proteins but also upregulating fatty acid oxidation and bile acid synthesis. Moreover, increasing studies found some potential targets to inhibit HBV replication or expression by decreasing or enhancing certain lipid metabolism-related proteins or metabolites. Therefore, in this article, we comprehensively reviewed these publications and revealed the connections between clinical observations and experimental findings to better understand the interaction between hepatic lipid metabolism and HBV infection. However, the available data are far from conclusive, and there is still a long way to go before clarifying the complex interaction between HBV infection and hepatic lipid metabolism.

Keywords: apolipoprotein; chronic hepatitis B; hepatic steatosis; hepatitis B virus; lipid metabolism; metabolic signaling pathway; nuclear factors.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
HBV-induced lipid metabolism changes in hepatocytes. HBV infection, replication, and expression in hepatocytes can change hepatic lipid metabolic pathways in many aspects. In HBV-transfected cell lines, HBV-transgenic mice or liver specimens from CHB patients, transcriptional factors (TF), and genes related to hepatic lipogenesis have changed much. Enhanced activation of LXR and SREBP1c increased downstream lipogenesis genes, including FAS, ACC, SCD, et al., and promoted free fatty acid (FFA) biosynthesis and lipogenesis (Kim et al., 2007; Yang et al., 2008; Zhang et al., 2013b; Wu et al., 2016; Xu et al., 2016; Bai et al., 2017; Wang et al., 2017). On the other hand, activation of LXR, C/EBP, PPARα and PPARγ can also increase FFA oxidation through adinonectin, or other ways (Yoon et al., 2011; Wang M.D. et al., 2016). Simultaneously, phosphatidylcholine synthesis was enhanced too (Huang et al., 2019). The key TF SREBP2 and enzyme HMGCR in the cholesterol synthesis pathway were stimulated by HBV replication or HBx protein, inducing increased cholesterol uptake and synthesis in hepatocytes (Li et al., 2013; Wang et al., 2018). The interaction between HBV and NTCP facilitated CYP7A1 expression and bile acid biosynthesis (Yan et al., 2012; Oehler et al., 2014; Eller et al., 2018). Moreover, HBV replication decreased the expression of several types of apolipoprotein (Apo), including ApoA1 (Zhang et al., 2013a; Jiang et al., 2014; Wang Y. et al., 2016), ApoA5 (Zhu et al., 2016), ApoB100 (Morita, 2016), or ApoC3 (Zhu et al., 2017), and repressed synthesis of HDL, LDL, VLDL in hepatocytes (Kang et al., 2004). While expression of ApoE (Shen et al., 2015) or ApoM (Gu et al., 2011) increased after HBV infection. Changes in hepatic lipid metabolism induced changed lipid levels in peripheral blood, including increased SFA and MUFA (Arain et al., 2018), decreased ApoA1, ApoA5, ApoB100, or ApoC3 (Wang et al., 2011; Jiang et al., 2014; Wang Y. et al., 2016; Zhu et al., 2016, 2017; Cui et al., 2019), or increased ApoE or ApoM (Gu et al., 2011; Shen et al., 2016). However, the level of TG and TC showed a decrease in CHB patients compared to normal controls (Wong et al., 2012; Cheng et al., 2013; Joo et al., 2017). The expression of genes in the red circle was increased, while that in the green circle was decreased. (ACBP, acetyl-CoA binding protein; ACC, acetyl-CoA carboxylase; ACSL, long-chain fatty acyl-CoA synthetase; Apo, apolipoprotein; C/EBPα, CCAAT/enhancer-binding protein; CYP7A1, cholesterol 7α-hydroxylase; FA, fatty acid; FABP, Fatty acid-binding protein; FAS, Fatty acid synthetase; HBV, hepatitis B virus; FAO, fatty acid oxidation; FXR, farnesoid X receptor; HBx, hepatitis B virus X protein; HBc, hepatitis B virus core protein; HDL, high density lipoprotein; HMGCR, hydroxymethylglutaryl coenzyme A reductase; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; LXR, liver X receptor; MUFA, monounsaturated fatty acid; NTCP, Na/taurocholate cotransporter; PL, phospholipid; PPAR, peroxisome proliferators-activated receptor; RXR, retinoid X receptor; SCD, stearoyl-CoA desaturase; SFA, saturated fatty acid; SM, Sphngomyelin; SREBP1c, sterol-regulatory element-binding protein1c; SREBP2, sterol regulatory element-binding protein 2; TC, total cholesterol; TG, triglyceride; VLDL, very low density lipoprotein).
FIGURE 2
FIGURE 2
Changes in proteins or metabolites of lipid metabolism pathway affect the life cycle of HBV: potential targets for HBV suppression. Firstly, inhibition of FAS activity decreased fatty acid (FA) synthesis and then suppressed HBV production and secretion (Zhang H. et al., 2013; Cho et al., 2014; Okamura et al., 2016). An increasing level of different FA would induce a different effect on HBV, such as promotion of HBV replication and expression by palmitate or stearate (Cho et al., 2014), while suppression of HBV by arachidonic acid (Song et al., 2018). As cholesterol is the necessary component of HBV particle, inhibition of HMGCR or SQLE decreased cholesterol biosynthesis and suppressed HBV production (Lin et al., 2003; Bremer et al., 2009). Increased HBV replication could be induced through LXR activation by oxysterols or FXR activation by bile acid (Ramière et al., 2008; Kim et al., 2011; Zhao et al., 2018). And inhibition of ApoE decreased HBV infection, production, or secretion (Qiao and Luo, 2019). Besides, decreasing PC synthesis inhibited HBV replication (Tatematsu et al., 2011; Li et al., 2015), and inhibition of RXR increased HBV infection (Reese et al., 2011). Red or green boxes indicated increased or decreased levels of lipid and lipid metabolism-related proteins, respectively. (Apo, apolipoprotein; FA, fatty acid; FAS, Fatty acid synthetase; FXR, farnesoid X receptor; HBV, hepatitis B virus; HMGCR, hydroxymethylglutaryl coenzyme A reductase; LXR, liver X receptor; PC, phosphatidylcholine; RXR, retinoid X receptor; SQLE, Squalene monooxygenase).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Alves-Bezerra M., Cohen D. E. (2017). Triglyceride Metabolism in the Liver. Comprehens. Physiol. 8 1–8. 10.1002/cphy.c170012 - DOI - PMC - PubMed
    1. Arain S. Q., Talpur F. N., Channa N. A., Ali M. S., Afridi H. I. (2018). Serum lipids as an indicator for the alteration of liver function in patients with hepatitis B. Lipids Health Dis. 17:36. 10.1186/s12944-018-0683-y - DOI - PMC - PubMed
    1. Bai P. S., Xia N., Sun H., Kong Y. (2017). Pleiotrophin, a target of miR-384, promotes proliferation, metastasis and lipogenesis in HBV-related hepatocellular carcinoma. J. Cell. Mol. Med. 21 3023–3043. 10.1111/jcmm.13213 - DOI - PMC - PubMed
    1. Bar-Yishay I., Shaul Y., Shlomai A. (2011). Hepatocyte metabolic signalling pathways and regulation of hepatitis B virus expression. Liver Int. 31 282–290. 10.1111/j.1478-3231.2010.02423.x - DOI - PubMed
    1. Bremer C. M., Bung C., Kott N., Hardt M., Glebe D. (2009). Hepatitis B virus infection is dependent on cholesterol in the viral envelope. Cell. Microbiol. 11 249–260. 10.1111/j.1462-5822.2008.01250.x - DOI - PubMed

LinkOut - more resources