Table 2.
Effects of natural antidiabetic compounds and synthetic antidiabetic drugs on PCSK9.
| Medicament Names |
Major antidiabetic mechanism |
Antidiabetic evidence |
Mechanism for PCSK9 inhibition |
Evidence for lowering PCSK9 |
Effects on LDLR |
Effects on lipid metabolism |
References |
|---|---|---|---|---|---|---|---|
| Synthetic inhibitors | |||||||
| Liraglutide | Activate GLP-1 receptor | In vitro, vivo, and clinical trials | Downregulated HNF-1α expression |
In vitro, in vivo, and clinical trials | Upregulate LDLR and mRNA | apoB48↓，TC↓， TG↓，LDL-C↓ |
[153,159,160,[174], [175], [176], [177]] |
| Metformin | AMPK-dependent and AMPK-independent mechanisms | In vitro, vivo, and clinical trials | Downregulate ChREBP expression |
In vitro, in vivo, and clinical trials | Upregulate LDLR and mRNA | LDL-C↓ | [163,167,168,178] |
| Kanglexin | Promote FGFR1/ERK signaling | In vitro | Downregulate SREBP2 expression |
In vitro and in vivo | Upregulate LDLR | TC↓TG↓ | [[169], [170], [171], [172], [173]] |
| Natural inhibitors | |||||||
| Polyphenols | |||||||
| EGCG | Inhibit NLRP3 pathway | In vitro and in vivo | Downregulate HNF-1αexpression |
In vitro, in vivo, and clinical trials | Upregulate LDLR and mRNA | LDL-C↓ | [[111], [112], [113], [114], [115], [116]] |
| Polydatin | Promote AMPK and Akt signaling, inhibit NF-kB | In vitro, in vivo, and clinical trails | Form hydrogen bonds with PCSK9 | In vitro and in vivo | Upregulate LDLR | LDL-C↓ | [[100], [101], [102], [103], [104],179] |
| Eugenol | Promote GLUT4-AMPK signaling | In vitro and in vivo | Unknown | In clinical trials | Unknown | LDL-C↓ | [[180], [181], [182], [183], [184]] |
| Naringin | Upregulate the FoxM1 and PDX-1 transcription factor | In vitro and in vivo | Downregulate SREBP2 expression |
In vivo | Upregulate LDLR | TC↓，TG↓， LDL-C， HDL-C↑ |
[[185], [186], [187]] |
| Quercetin | Promote the MAPK AMPK AGE-RAGE signaling |
In vitro and in vivo | Inhibits secretion and SREBP2 |
In vitro and in vivo | Unknown | TC↓，TG↓， LDL-C↓， HDL-C↑ |
[[188], [189], [190], [191], [192], [193], [194]] |
| Quercetin-3-glucoside | Inhibit NF-kB signaling | In vitro and in vivo | Attenuate PCSK9 secretion |
In vitro and in vivo | Upregulate LDLR and mRNA | TC↓，TG↓， LDL-C↓， HDL-C↑ |
[[195], [196], [197], [198], [199], [200]] |
| Pterostilbene | Promote AMPK, PI3K/Akt, and Nrf2 signaling | In vitro, in vivo, and clinical trails | Downregulate SREBP2 and HNF1-α expression | In vitro | Upregulate LDLR and mRNA | TC↓，TG↓， VLDL-C↓， LDL-C↓ |
[[93], [94], [95],[97], [98], [99]], [[201], [202], [203], [204]] |
| Resveratrol | Promote AMPK, PI3K/Akt/FoxO3a, Nrf2, SIRT/FOXO signaling | In vitro, in vivo, and clinical trails | Downregulate SREBP1-c expression | In vitro | Upregulate LDLR | TC↓，TG↓ | [[205], [206], [207], [208], [209], [210], [211]] |
| Curcumin | Promote AMPK and MAPK signaling. Inhibit NF-kB | In vitro, in vivo, and clinical trials | Downregulate HNF1-α expression |
In vitro | Upregulate LDLR | TC↓，TG↓， LDL-C↓， HDL-C↑ |
[[212], [213], [214], [215]] |
| Isoquinoline alkaloids | |||||||
| Berberine | Promote AMPK and MAPK signaling | In vitro, vivo, and clinical trials | Promote HNF1-α degradation | In vitro, in vivo, and clinical trials | Upregulate LDLR and mRNA | TC↓，TG↓， LDL-C↓， HDL-C↑ |
[4,[122], [123], [124], [125], [126], [127], [128], [129], [130], [131], [132],136,138,[216], [217], [218]] |
| 9 k | Unknown | Unknown | Downregulate HNF1-α and sp1 expression | In vitro | Upregulate LDLR | LDL-C↓ | [138] |
| Anthraquinones | |||||||
| Emodin | Downregulate SREBPs expression | In vivo and in vitro | Unknown | In vivo | Upregulate LDLR | TC↓，TG↓， LDL-C↓， HDL-C↑ |
[145,[149], [150], [151], [152]] |