Abstract
Non-alcoholic fatty liver disease (NAFLD) has become a progressive metabolic disease that is emerging as a global epidemic. Considering that the complex pathogenesis has not been fully elucidated, barely specific pharmacological therapy is recommended in current guidelines. Gentiana scabra (GS) is a commonly used herb in Tibetan medicine, which has received much attention in recent years due to its diverse pharmacological properties, including anti-inflammation, anti-oxidation, and anti-fibrosis. However, the therapeutic mechanisms are still unclear. Our investigation demonstrated a regulatory effect of GS on pro-inflammatory macrophages, which was extensively investigated in NAFLD that revealed intimate participation in the disease evolution, and the non-canonical IKK family member TANK-binding kinase 1 (TBK1) was involved in this process. Plasmid vectors for shTBK1 and amlexanox (AML), an inhibitor of TBK1, were used in this study to verify the mechanisms of TBK1 both in vitro and in vivo, while a co-culture system for hepatocytes and BMDMs was constructed to confirm the critical role of macrophages for inflammatory cascade. The results revealed that metabolic burden up-regulated the phosphorylation of TBK1, resulting in activation of NF-κB signaling pathway, and consequently caused an elevated expression of MCP1 to induce the macrophage recruitment and accelerate the inflammatory cascade. In contrast, GS could inhibit the TBK1 phosphorylation and the MCP1 expression to restrain the recruitment of pro-inflammatory macrophages, so as to provide curative effects on metabolic dysfunction and inflammation. Considering that GS is non-toxic and can be used as a kind of tea for long-term drinking, we propose it may be an effective option for the prevention and treatment of NAFLD, which deserves further exploration and application, and may provide new insights to improve the current standardized intervention strategy.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome closely related to obesity, insulin resistance, and many other metabolic diseases
708 putative targets were achieved under the conditions of degree centrality (DC) > 32, and an inflammation-related signaling network including TANK-binding kinase 1 (TBK1) was found to occupy a large part in the network (Figures 1C,D)
NAFLD is a clinicopathological syndrome caused by intrahepatic fat accumulation, and comprises a continuum of liver pathologies ranging from steatosis to steatohepatitis, including fibrosis and cirrhosis (Eslam et al, 2020)
Summary
Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome closely related to obesity, insulin resistance, and many other metabolic diseases. It has been defined as metabolic-associated fatty liver disease (MAFLD) in the latest international expert consensus statement (Eslam et al, 2020). There is barely specific pharmaceutical therapy recommended for the treatment of NAFLD in current guidelines, research on new therapeutic strategies is urgently needed (Aller et al, 2018). Gentiana scabra (GS), a commonly used herb in Tibetan medicine, is the flower of Gentian and possesses multiple pharmacological effects, such as anti-bacterial, anti-viral, antitumor, etc.; besides these, many other therapeutic functions have taken more place in recent years, including anti-inflammation, anti-oxidation, and anti-fibrosis (Li et al, 2008; Geng et al, 2010; Khobrakova et al, 2017). Considering that GS is non-toxic and can be used as a kind of tea for long-term drinking, we propose it is an effective option for the prevention and treatment of NAFLD, and there is an imperative need to clarify the pharmacological mechanism to promote its clinical application
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