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Recent advances in research on natural product inhibitors of SREBPs

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Abstract

Sterol regulatory element-binding proteins (SREBPs) are a class of cholesterol-sensitive transcription factors that play important roles in lipid metabolism. Natural product inhibitors of SREBPs have been shown to inhibit the synthesis of free fatty acids and cholesterol, promote the burning of brown fat, and relieve insulin resistance by inhibiting different links during the synthesis, cleavage, and transport of SREBPs, thereby improving obesity, diabetes, atherosclerosis, and other metabolic diseases and disorders. There are numerous Chinese herbal medicines with verified efficacy in the treatment of metabolic diseases, including Coptis chinensis Franch. and Pueraria peduncularis Grah. for diabetes, Pueraria peduncularis Grah., Epimedium brevicornum Maxim., and Panax ginseng C. A. Meyer for osteoporosis, and Nelumbo nucifera Gaertn. and Poria cocos (Schw.) Wolf. for obesity. Present-day research on the mechanisms underlying the activity of traditional Chinese medicine has indicated that certain chemical components of these traditional preparations can be used to treat metabolic diseases by inhibiting SREBPs. Progress in the research on natural product SREBP inhibitors is continuing apace, and the mechanisms of action of certain small molecules have become well established. In this study, we review recent progress in the research on natural small-molecule inhibitors of SREBPs, including flavonoids, saponins, triterpenoids, and alkaloids, which we hope will provide a useful reference for future research and development of drugs for the treatment of metabolic diseases.

Highlights

This paper reviews progress in research on natural small-molecule inhibitors of sterol regulatory element-binding proteins derived from traditional Chinese herbal medicines, including flavonoids, saponins, triterpenoids, etc., in the therapy of obesity, diabetes, atherosclerosis, and other metabolic diseases.

The benefits and drawbacks of natural SREBP inhibitors in the treatment of metabolic disease

As illustrated by the examples covered in this review, natural inhibitors of SREBPs have considerable potential with respect to the treatment of debilitating diseases and can provide novel solutions to multiple medical problems. SREBPs have been established to represent a causal link between abnormal fat and cholesterol generation and the occurrence and development of cancer [74], and accordingly, compounds that function as SREBP inhibitors are identified as potentially novel sources of anti-cancer therapy. In addition, researchers have found that by inhibiting cell mitosis, these inhibitors can also reduce the survival rate of cancer cells, which provides a new solution for the treatment of those cancers that are resistant to currently used anti-cancer drugs, such as glioblastomas that are characterized by rapid rates of lipid metabolism and proliferation [79]. Consequently, the application of SREBP inhibitors in joint studies on metabolism and cancer would be anticipated to promote dual developments in both the fields. However, given that SREBPs play roles in multiple signaling pathways, the inhibitors of these SREBPs may have simultaneous and potentially differential effects on different processes. For example, among SREBPs involved in innate immune responses, SREBP-1a not only contributes to the activation of genes necessary for fat generation in macrophages but also those encoding NLRPLa, the core component of the inflammatory response [80]. Consequently, when using SREBP inhibitors for therapeutic purposes, it is vital to carefully assess the potential influence on multiple pathways. Accordingly, prior to any therapeutic application of SREBP inhibitors, there needs to be comprehensive toxicity investigations and assessments of potential effects on non-target sites to ensure drug safety.

Classification of small molecule inhibitors of natural products of SREBPs
  1. Saponins
    • Pseudoprotodioscin
    • Kudinoside-D
    • Ginsenoside Re
    • Arctiin
    • Phillyrin
  2. Flavonoids
    • Quercetin
    • Anhydroicaritin
    • Xanthohumol
    • Gabridin
    • Formononetin
  3. Alkaloids
    • Berberine
    • Tomatidine
    • Sophocarpine
    • Caffeine
    • Rohitukine
  4. Terpenoids
    • Carnosic acid
    • Chlorogenic acid
    • Ursolic acid
    • Celastrol
    • Andrographolide
  5. Others
    • Allyl isothiocyanate
    • Syringic acid
    • Curcumin
    • Ligustrazine
    • Betulinol

https://doi.org/10.53388/TMR20220214264

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