Investigation of the Lipid-Lowering Mechanisms and Active Ingredients of Danhe Granule on Hyperlipidemia Based on Systems Pharmacology

Abstract

Objective: Investigate the active ingredients and underlying hypolipidemic mechanisms of Danhe granule (DHG). Methods: The lipid-lowering effect of DHG was evaluated in hyperlipidemic hamsters induced by a high-fat diet. The ingredients absorbed into the blood after oral administration of DHG in hamsters were identified by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). A systems pharmacology approach incorporating target prediction and network construction, gene ontology (GO) enrichment and pathway analysis was performed to predict the active compounds and map the compounds-targets-disease network. Real-time polymerase chain reaction (RT-PCR) and Western blot were utilized to analyze the mRNA and protein expression levels of predicted targets. Results: DHG remarkably lowered the levels of serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), and arteriosclerosis index (AI), at the same time, elevated the levels of serum high-density lipoprotein cholesterol (HDL-c) and HDL-c/TC ratio in hyperlipidemic hamsters. Sixteen ingredients absorbed into blood after oral administration of DHG were identified as the possible components interacted with targets. Moreover, 65 potential targets were predicted after targets intersection and compounds-targets-disease network mapping. Then, compounds-targets-pathways network mapping revealed that six active compounds (emodin, naringenin, etc.) compounds could interact with 10 targets such as sterol regulatory element binding protein (SREBP) 1c, SREBP-2 and peroxisome proliferation-activated receptor (PPAR) a, regulate three lipid metabolism-related pathways including SREBP control of lipid synthesis pathway, PPAR signaling pathway and nuclear receptors in lipid metabolism and toxicity pathway, and further affect lipid metabolic processes including fatty acid biosynthesis, low-density lipoprotein receptor (LDLR)-mediated cholesterol uptake, bile acid biosynthesis, and cholesterol efflux. Experimental results indicated that DHG significantly increased SREBP-2, LDLR, PPARa, liver X receptor alpha (LXRa),

Effect of Emodin on Hyperlipidemia and Hepatic Lipid Metabolism in Zebrafish Larvae Fed a High‐Cholesterol Diet**

“…Traditional Chinese Medicine have been applied for treatment of various diseases including HLP and cardiovascular disease with a history of more than 2000 years. Chen indicated that Danhe Granule, a traditional Chinese medicine formula, exhibited excellent hypolipidemic effects in diet‐induced HLP hamsters [39] . Meanwhile, they isolated and identified six active components including EM in the hamster blood, and found that these active components may modulate some key targets (SREBP‐1, SPEBP‐2, LDLR, and so on) involved in lipid metabolism‐related pathways through systemic pharmacological analysis.…”

Effects of Different Treatment Methods of Dried Citrus Peel (Chenpi) on Intestinal Microflora and Short-Chain Fatty Acids in Healthy Mice

“…Other studies also have shown that chenpi can reduce the gain of body weight, organ weight, and accumulation of lipid ( 37 ). Obesity is closely related to hyperlipidemia, and reducing the content of serum triglyceride can effectively alleviate hyperlipidemia ( 38 ). There was no significant change in body weight and liver weight in our study, perhaps because the feeding time was not long enough.…”

Identifying selective agonists targeting LXRβ from terpene compounds of alismatis rhizoma

“…Previous studies showed that activation of LXR activity could reduce TC, which is responsible for hyperlipidemia [8,1]. Many LXRβ agonists have already been screened such as T0901317 and LXR623 [62,63].…”

“…One of the causes of hyperlipidemia is high level of TC, which is tightly regulated by liver X receptor (LXR) [1,8]. LXR is a nuclear receptor with two isoforms, LXRα and LXRβ.…”