Therapeutic potential of PPARγ natural agonists in liver diseases

Abstract Peroxisome proliferator‐activated receptor gamma (PPARγ) is a vital subtype of the PPAR family. The biological functions are complex and diverse. PPARγ plays a significant role in protecting the liver from inflammation, oxidation, fibrosis, fatty liver and tumours. Natural products are a promising pool for drug discovery, and enormous research effort has been invested in exploring the PPARγ‐activating potential of natural products. In this manuscript, we will review the research progress of PPARγ agonists from natural products in recent years and probe into the application potential and prospects of PPARγ natural agonists in the therapy of various liver diseases, including inflammation, hepatic fibrosis, non‐alcoholic fatty liver and liver cancer.


| MOLECUL AR S TRUC TURE OF PEROXISOME PROLIFER ATOR-AC TIVATED RECEP TOR G AMMA (PPARγ)
The PPARs belongs to the superfamily of nuclear hormone receptors and is named for its activation, which is regulated by the peroxisome proliferators. There are three subtypes of PPARs (PPARα, PPARβ and PPARγ). These three subtypes of PPARs are expressed differently in different tissues. PPARα is mainly manifested in cardiomyocytes, he-

patocytes, intestinal epithelial cells and renal tubule epithelial cells;
PPARβ is found in many tissues, with the higher expression in the intestine, kidney and heart; and PPARγ is mainly expressed in adipose

| FUN C TI ON AND CELLUL AR ROLE S OF PPA Rγ
The biological functions of PPARγ are complex and diverse, including regulation of lipid and carbohydrate metabolism, energy balance, inhibiting inflammation, inducing tumour cell differentiation and apoptosis, inhibiting tumour angiogenesis, anti-fibrosis and anti-atherosclerosis, reducing blood fat and blood pressure, improving heart failure and participating in ventricular remodelling. Thus, PPARγ is a current focus of research present. And indeed, there are a number of researchers, who have written review articles to shed more light on the power of PPARγ.
Semple reviewed the function of PPARγ and its variants in metabolic syndrome. 1 In addition, Jia, 4 Chigurupati 5 and Vallée 6 analysed therapeutic potential of PPARγ agonists in diabetes. PPARγ agonists improve insulin sensitivity and treat complications of diabetes. PPARγ can stimulate the differentiation of pre-adipocytes into mature adipocytes and is closely related to adipogenesis in mature adipocytes. 7 The beneficial role of PPARγ in regulation immunity was summarized by Samuel Philip Nobs, 8 Chung, 9 Abdelrahman, 10 Giaginis 11 and Staels. 12 PPARγ inhibits pro-inflammatory responses by macrophages, DCs, and T cells. Reka, 13 Lecarpentier 14 21 Additional results confirmed that decreased expression of PPARγ was found in activated hepatic stellate cells (HSCs), suggesting that the increased expression and activity of PPARγ promoted the recovery of activated HSCs to a resting state. [22][23][24][25] Among the multiple biological responses involved, PPARγ plays a corresponding role by regulating the expression of signalling pathways, including JAK-STAT, NF-kB, nuclear factor of activated T cell, AP-1, PI3K, leptin and adiponectin. Therefore, PPARγ is of vital importance when making a diagnosis and selecting treatment for related diseases.

| PPA Rγ AGONIS TS FROM NATUR AL PRODUC TS
Because of the significant role of PPARγ in diseases, the identification of PPARγ agonists is regarded as targets of numerous drug development works. Large amounts of fatty acids and fatty acid derivatives can activate PPARγ. Among the PPARγ activators, long-chain polyunsaturated fatty acids always show better effects, such as eicosanoids [8-S-hydroxyeicosatetraenoic acid and leukotriene B4]. Also, PPARγ can be activated by several prostanoids, such as 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2) and 15-hydroxyeicosatetraenoic acid. The effect of 15d-PGJ2 has been widely recognized. 11 Thiazolidinediones (TZDs) are synthetic ligands of PPARγ and are well-known for excellent potency in regulating blood glucose levels and insulin sensitivity. 26 However, the undesirable side effects, such as fluid retention, weight gain, cardiac hypertrophy and hepatotoxicity, have limited the clinical use of TZDs. 5 Thus, searching for drugs with a similar clinical function, but fewer side effects has become a new direction of effort. Natural products are rich sources of drug discovery; thus, natural products are a focus of research. 27,28 Previous studies have successfully demonstrated various PPARγ agonists from natural resources by using reporter gene assays, pharmacophore models, silicon screening and virtual screening approaches. A cell-based luciferase reporter system may become a suitable method to detect bioavailability of nuclear receptors, including PPARs. 29 36,37 and some databases, 36 to find novel agonists as potential candidates to treat diseases. 38 The functionality of some approaches has been verified.
To review PPARγ agonists from natural products we checked the database, DrugBank (www.drugb ank.ca), which combines bio-and chem-informatics. Not surprisingly, an abundance of research efforts has been undertaken to explore the potential applications of full or partial PPARγ natural agonists. Table 2  Meanwhile, there are new trends in the treatment of liver disease which are using dual PPARα/γ or PPAR δ/γ agonists and pan agonists to enhance treatment efficacy. 39,40 Of note, synthetic dual or pan PPAR agonists were discontinued due to adverse events. 41 It has been showed that resveratrol, 42 carvacrol, 43 osthole, 44 dark tea extracts, 45 isoprenols, 46 pseudolaric acid B, 47 mulberry leaf water extract, Korean red ginseng, banaba leaf water extract, 48 and cannabinoids 49 activate two or three isotypes of PPARs, and can therefore be used for regulate metabolism. And the compound functions are discussed below.
The liver is the centre of bio-transformation and detoxification of numerous metabolites and toxicants. Exposure to high levels of exogenous or endogenous toxins may lead to liver damage, which ranges from a transient elevation of liver enzymes to hepatic inflammation, fibrosis, cirrhosis and cancer. Although the expression of PPARγ is always at a low level in liver, PPARγ agonists exhibit various PPARγ-dependent or PPARγ-independent effects in liver. 50 In addition, researches on our team have focused on the prevention and therapy of liver diseases in recent years. We also have published some reports on the effects of PPARs in liver diseases.
In fact, some of the Chinese herbal medicines or plants extracts have been reported to have a close relationship with PPARs, and a range of PPARγ activating natural products were recently recognized that possess a great potential to be further explored for the therapeutic effectiveness in liver diseases; but it has not thoroughly reviewed, and its natural agonists have been evaluated even less. Even, few reviews of the effects of PPARγ natural agonists in liver disease have been published. Understanding the role natural products play, as well as their therapeutic potential for fighting liver diseases, including hepatitis, fibrosis, fatty liver and liver cancer, is critical for future progress. Therefore, our present review summarizes the latest research progress of PPARγ agonists from natural products in recent years and explores the application prospect of PPARγ natural agonists in the treatment of liver diseases.

| PPARγ natural agonists in hepatitis-associated inflammation
Inflammation is provoked by pathogenic agents, physical or chemical harm, and ischaemic or autoimmune injury, and it is a vital response for protection. The role of PPARγ in the regulation of inflammatory responses has received particular attention. PPARγ appears to be expressed in many cell types of the immune system, such as macrophages, dendritic cells, platelets, T cells and B cells. 59 In addition, PPARγ has been shown in numerous studies to affect the expression of pro-inflammatory, anti-inflammatory and pro-resolving cytokines. 60

| PPARγ natural agonists in liver fibrosis
Liver fibrosis is a chronic and dynamic pathophysiological process, and commonly, excessive secretion and deposition of matrix proteins by HSCs is a pivotal step. Liver fibrosis is closely connected with hepati-

| PPARγ natural agonists in liver cancer
More than one decade ago, PPARγ was reported to be closely re-   169,170,172,[193][194][195][196] Kaempferia parviflora, Moringa concanensis Nimmo, Resveratrol 2019 42,95,197,198 signalling. The animal experiments showed that hispidulin administration could suppress tumour growth and lung metastasis. 89 Huangs The studies on the favourable effects of PPARγ natural agonists for HCC were few, and researches for several other types of cancer are listed in Table 3. 16,[92][93][94] To some extent, they can also demonstrate the potential of PPARγ natural agonists as anti-liver cancer agents.

| PPARγ natural agonists in non-alcoholic fatty liver disease (NAFLD)
Fatty liver disease, due to input/output imbalance of hepatic free fatty acid(FFA) metabolism, is regarded as one of the most common chronic liver diseases worldwide. Insulin resistance and oxygen stress are regarded as the central to development. The multi-layer and multi-angle function of PPARγ have been confirmed by many researchers. 95

CO N FLI C T O F I NTE R E S T S
The authors report no conflicts of interest in the present study.

DATA AVA I L A B I L I T Y S TAT E M E N T
All data included in this study are available.