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Review
, 10 (1), 3-18

Herbal Drug Discovery for the Treatment of Nonalcoholic Fatty Liver Disease

Affiliations
Review

Herbal Drug Discovery for the Treatment of Nonalcoholic Fatty Liver Disease

Tingting Yan et al. Acta Pharm Sin B.

Abstract

Few medications are available for meeting the increasing disease burden of nonalcoholic fatty liver disease (NAFLD) and its progressive stage, nonalcoholic steatohepatitis (NASH). Traditional herbal medicines (THM) have been used for centuries to treat indigenous people with various symptoms but without clarified modern-defined disease types and mechanisms. In modern times, NAFLD was defined as a common chronic disease leading to more studies to understand NAFLD/NASH pathology and progression. THM have garnered increased attention for providing therapeutic candidates for treating NAFLD. In this review, a new model called "multiple organs-multiple hits" is proposed to explain mechanisms of NASH progression. Against this proposed model, the effects and mechanisms of the frequently-studied THM-yielded single anti-NAFLD drug candidates and multiple herb medicines are reviewed, among which silymarin and berberine are already under U.S. FDA-sanctioned phase 4 clinical studies. Furthermore, experimental designs for anti-NAFLD drug discovery from THM in treating NAFLD are discussed. The opportunities and challenges of reverse pharmacology and reverse pharmacokinetic concepts-guided strategies for THM modernization and its global recognition to treat NAFLD are highlighted. Increasing mechanistic evidence is being generated to support the beneficial role of THM in treating NAFLD and anti-NAFLD drug discovery.

Keywords: Fatty liver; Metabolic syndrome; NAFLD; Natural products; TCM.

Figures

Image 1
Figure 1
Figure 1
Proposed “multiple organs-multiple hits” model for explaining the NAFLD/NASH pathogenesis. “Multiple organs-multiple hits” model describes how the crosstalk between liver and other tissues/non-liver cells (gut, brown/white adipose, skeletal muscle, brain and macrophages) promotes NASH progression. Free fatty acids, sourced from either adipose lipolysis or hepatic lipid droplets or de novo lipogenesis from dietary fats/sugars, overload the liver. Then, fatty acids could be degraded by fatty acid β-oxidation and triglyceride secreted from liver to serum, or can be converted to lipotoxic lipids when the disposal pathways of fatty acids are saturated. Lipotoxic lipids could then cause oxidative stress, ER stress, inflammation and possibly cell death. Non-liver organs can also contribute directly or indirectly to NASH progression. During NAFLD progress, changes in gut microbiota composition or intestinal lipids modulation signaling, can yield toxic microbiota products, or even forms leaky gut to release LPS or bacteria, all of which could be PAMPs or DAMPs and enter the liver via the portal vein. All the PAMPs and/or DAMPs generated from liver, gut or macrophages can work together to activate HSC and cause liver fibrosis. Energy balance could be regulated by the central nervous system via food intake or central hormones/signaling, as well as by brown adipose or skeletal muscle that helps burn adipose fat via thermogenesis or energy expenditure, thus indirectly decrease the overloaded burden of hepatic fatty acids and alleviate NAFLD.
Figure 2
Figure 2
Chemical structures of frequently-examined THM-derived components for the treatment of NAFLD in clinical trials registered at Clinicaltrials.gov. Compounds A–G are hepatoprotective components isolated from silymarin, while curcumin (H), resveratrol (I) and berberine (J) belong to single compound drug.
Figure 3
Figure 3
Role and mechanisms of frequently-studied traditional herbs in treating NAFLD. Four frequently-studied THM (silymarin, curcumin, berberine, and resveratrol) are registered in ClinicalTrials.gov for clinically testing their safety and efficacy in treating NAFLD. Berberine and silymarin were subjected to a phase 4 clinical trial. These four representative traditional herbs show hepatoprotective effects in improving NAFLD/NASH in preclinical rodent mouse models via various molecular pathways mainly including cell death modulation (via inducing autophagy or inhibiting hepatocyte apoptosis), lipid metabolism modulation (via activating FXR, PPARA, PPARG, AMPK, SIRT1 or antagonizing LXR), anti-inflammation (via inhibiting TLR/MYD88 or NLRP3 inflammasome pathway), anti-oxidative stress (via activating NRF2), modulating liver-gut axis (via changing microbiota composition, repairing leaky gut to reduce the release of LPS or harmful bacteria, modulating intestinal FXR signaling or SIRT1 signaling, or producing microbiota products such as active bile acids or herb drug metabolites).

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References

    1. Wree A., Broderick L., Canbay A., Hoffman H.M., Feldstein A.E. From NAFLD to NASH to cirrhosis—new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol. 2013;10:627–636. - PubMed
    1. Michelotti G.A., Machado M.V., Diehl A.M. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 2013;10:656–665. - PubMed
    1. Zhu J.Z., Dai Y.N., Wang Y.M., Zhou Q.Y., Yu C.H., Li Y.M. Prevalence of nonalcoholic fatty liver disease and economy. Dig Dis Sci. 2015;60:3194–3202. - PubMed
    1. Fan J.G., Kim S.U., Wong V.W. New trends on obesity and NAFLD in Asia. J Hepatol. 2017;67:862–873. - PubMed
    1. Younossi Z., Anstee Q.M., Marietti M., Hardy T., Henry L., Eslam M. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11–20. - PubMed

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