Clinical Evidence and Potential Mechanisms of Complementary Treatment of Ling Gui Zhu Gan Formula for the Management of Serum Lipids and Obesity

Abstract

Objective: This study aims to evaluate the clinical effects of Ling Gui Zhu Gan formula (LGZG), a famous TCM formula, for the management of serum lipids and obesity and preliminarily elucidates the bioactive components and the potential mechanism.

Methods: Cluster analysis was adopted to investigate the TCM herbs and their frequency of occurrence for treating hyperlipidemia and obesity in an academic experience database of Chinese famous TCM doctors (http://www.gjmlzy.com:83). Then, relevant randomized controlled trials (RCTs) about LGZG supplementation in improving lipid levels and obesity were retrieved and analyzed. Lastly, the integration of network pharmacology, as well as greedy algorithms, which are theoretically well founded for the set cover in computer science, was exploited to identify the bioactive components of LGZG and to reveal potential mechanisms for attenuation or reversal of hyperlipidemia and obesity.

Results: Based on the cluster analysis of 104 cases in TCM academic experience database, four TCM herbs in LGZG showed high-use frequency for treating hyperlipidemia and obesity. Meta-analysis on 19 randomized controlled trials (RCTs) with 1716 participants indicated that LGZG supplementation significantly decreased the serum levels of total triglycerides, total cholesterol, low-density lipoprotein cholesterol, BMI, and body weight and increased high-density lipoprotein cholesterol, compared with clinical control groups. No serious adverse effect was detected in all studies. Twenty-one bioactive components of LGZG, mainly flavonoids (i.e., naringenin, kaempferol, and kumatakenin), saponins (i.e., hederagenin), and fatty acids (i.e., eicosenoic acid), had the potential benefits possibly by regulating multiple targets such as PTPN1, CYP19A1, and ESR2, as well as a few complex pathways including the TNF signaling pathway, PPAR signaling pathway, arachidonic acid metabolism, fat digestion, and absorption.

Conclusion: The present study has proved the clinical value of LGZG as a complementary treatment for attenuation or reversal of hyperlipidemia and obesity. More high-quality clinical and experimental studies in the future are demanded to verify its effects and the precise mechanism of action.

Figure 1

Cluster analysis of 104 cases associated with hyperlipidemia/dyslipidemia and obesity using an academic experiences database of Chinese famous TCM doctors (http://www.gjmlzy.com:83) and the herbs composition of LGZG.

Figure 2

Flow diagram of records inclusions.

Figure 3

The risk of methodological bias. (a) The risk of bias summary: authors' judgments about each risk of bias item for each included study; (b) the risk of bias graph.

Figure 4

Forest plot of the effect of LGZG on the effective rate.

Figure 5

Forest plot of the effects of LGZG on serum lipid parameters of TG (a), TC (b), LDL-c (c), and HDL-c (d).

Figure 6

Forest plot of the effects of LGZG on obesity parameters of BMI (a), BW (b), and WC (c).

Figure 7

Targets identification of LGZG for obesity and hyperlipidemia/dyslipidemia. (a) Venn diagram; (b) protein-protein interaction network.

Figure 8

GO and KEGG enrichment analyses of key targets in LGZG for management of serum lipid and obesity (top 20).

Figure 9

Construction of herb-component-target-pathway network to reveal the regulatory mechanism of LGZG on hyperlipidemia and obesity (a). The red circles, yellow hexagon, and orange diamonds represent the four herbs, active components of LGZG, and diseases, respectively. The green circles represent targets related to LGZG and diseases, and blue V's represent the related pathways. (b) Minimized set of components (red diamond) and targets (cyan circles) network based on greedy algorithms.

Figure 10

The top five components with higher degree of values in the component-target network, including (a) eicosenoic acid (C₂₀H₃₈O₂, molecular weight: 310.5), (b) naringenin (C₁₅H₁₂O₅, molecular weight: 272.25), (c) kaempferol (C₁₅H₁₀O₆, molecular weight: 286.24), (d) hederagenin (C₃₀H₄₈O₄, molecular weight: 472.7), and (e) kumatakenin (C₁₇H₁₄O₆, molecular weight: 314.29).5.