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. 2024 Jan 19;10(3):e24908.
doi: 10.1016/j.heliyon.2024.e24908. eCollection 2024 Feb 15.

Lipid regulation of protocatechualdehyde and hydroxysafflor yellow A via AMPK/SREBP2/PCSK9/LDLR signaling pathway in hyperlipidemic zebrafish

Bingying Lin  1 , Haofang Wan  2 , Jiehong Yang  1 , Li Yu  1   3   4 , Huifen Zhou  1   3   4 , Haitong Wan  1   3   5   4
Affiliations

Lipid regulation of protocatechualdehyde and hydroxysafflor yellow A via AMPK/SREBP2/PCSK9/LDLR signaling pathway in hyperlipidemic zebrafish

Bingying Lin et al. Heliyon. .

Abstract

The consumption of a high-cholesterol diet is known to cause hyperlipidemia, which is one of the main risk factors for cardiovascular disease. Protocatechualdehyde (PCA) and hydroxysafflor yellow A (HSYA) are the active components of Salvia miltiorrhiza and safflower, respectively. However, their exact mechanism is still unclear. The aim of this study is to investigate its effects on lipid deposition and liver damage in hyperlipidemic zebrafish and its mechanism of anti-hyperlipidemia. The results showed that the use of PCA and HSYA alone and in combination can improve lipid deposition, slow behavior, abnormal blood flow and liver tissue damage, and the combined use is more effective. Further RT-qPCR results showed that PCA + HSYA can regulate the mRNA levels of PPAR-γ, SREBP2, SREBP1, HMGCR, PCSK9, mTOR, C/EBPα, LDLR, AMPK, HNF-1α and FoxO3a. The PCA + HSYA significantly improves lipid deposition and abnormal liver function in hyperlipidemic zebrafish larvae, which may be related to the AMPK/SREBP2/PCSK9/LDLR signaling pathway.

Keywords: Hydroxysafflor yellow A; Hyperlipidemia; Protocatechualdehyde.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Toxic phenotype of zebrafish larvae. (A)No obvious abnormality, (B)uninflated swim bladder, (C)pericardial edema, (D)spinal curvature and (E)death. Magnification: (A–C)20 × , (D)15 × and (E)7 × .
Fig. 2
Fig. 2
Sim, PCA, HSYA and PCA + HSYA all decreased lipid accumulation in the caudal vein. (A) Oil red O staining of zebrafish larvae. (B)IOD values. The Control group; HCD group; PCA-L, HCD + PCA 25 μg/mL; PCA-M, HCD + PCA 50 μg/mL; PCA-H, HCD + PCA 100 μg/mL; HSYA-L, HCD + HSYA 25 μg/mL; HSYA-M, HCD + HSYA 50 μg/mL; HSYA-H, HCD + HSYA 100 μg/mL; PCA + HSYA-L, HCD + PCA 25 μg/mL + HSYA 25 μg/mL; PCA + HSYA-M, HCD + PCA 50 μg/mL + HSYA 50 μg/mL; PCA + HSYA-H, HCD + PCA 100 μg/mL + HSYA 100 μg/mL ###P < 0.001, in comparison with the Control group. ***P < 0.001, in comparison with the HCD group, and the error bars represent SD. Magnification: (A)20 × and 45 × .
Fig. 3
Fig. 3
Effects of PCA, HSYA and PCA + HSYA administration on HCD-induced hyperlipidemia in zebrafish larvae. The Control group; HCD group; PCA-L, HCD + PCA 25 μg/mL; PCA-M, HCD + PCA 50 μg/mL; PCA-H, HCD + PCA 100 μg/mL; HSYA-L, HCD + HSYA 25 μg/mL; HSYA-M, HCD + HSYA 50 μg/mL; HSYA-H, HCD + HSYA 100 μg/mL; PCA + HSYA-L, HCD + PCA 25 μg/mL + HSYA 25 μg/mL; PCA + HSYA-M, HCD + PCA 50 μg/mL + HSYA 50 μg/mL; PCA + HSYA-H, HCD + PCA 100 μg/mL + HSYA 100 μg/mL. Histogram of (A)TC, (B)LDL-C, (C)TG and (D)HDL-C in zebrafish larvae. ###P < 0.001, in comparison with the Control group. *P < 0.05, ***P < 0.001, compared with the HCD group, and the error bars represent SD.
Fig. 4
Fig. 4
Behavior evaluation of zebrafish larvae in each group. The Control group; HCD group; PCA-H, HCD + PCA 100 μg/mL; HSYA-H, HCD + HSYA 100 μg/mL; PCA + HSYA-H, HCD + PCA 100 μg/mL + HSYA 100 μg/mL (A)Behavioral trajectories of each group of zebrafish larvae. (B)Graphical representation of total distance moved (mm) of treated larvae in the Control, HCD, PCA-H, HSYA-H and PCA + HSYA-H groups. (C)Graphical representation of the mean velocity (mm/s) of treated larvae in the Control, HCD, PCA-H, HSYA-H and PCA + HSYA-H groups. ###P < 0.001, in comparison with the Control group. *P < 0.05, **P < 0.01, in comparison with the HCD group, and the error bars represent SD.
Fig. 5
Fig. 5
Hemodynamic evaluation of zebrafish larvae. The Control group; HCD group; PCA-H, HCD + PCA 100 μg/mL; HSYA-H, HCD + HSYA 100 μg/mL; PCA + HSYA-H, HCD + PCA 100 μg/mL + HSYA 100 μg/mL. The flow activity of zebrafish larvae in the (A)Control, (B)HCD, (C)PCA-H, (D)HSYA-H and (E)PCA + HSYA-H groups. (F)Histogram representation of flow activity. ###P < 0.001, in comparison with the Control group, and the error bars represent SD.
Fig. 6
Fig. 6
PCA, HSYA and PCA + HSYA can reduce AST and ALT levels. The Control group; HCD group; PCA-H, HCD + PCA 100 μg/mL; HSYA-H, HCD + HSYA 100 μg/mL; PCA + HSYA-H, HCD + PCA 100 μg/mL + HSYA 100 μg/mL (A-B)Zebrafish larvae fed HCD were given PCA, HSYA and PCA + HSYA, and AST and ALT levels were measured. ###P < 0.001 in comparison with the Control group; ***P < 0.001, in comparison with the HCD group, and the error bars represent SD.
Fig. 7
Fig. 7
Pathological observation of the liver in each group of zebrafish larvae. The Control group; HCD group; PCA-H, HCD + PCA 100 μg/mL; HSYA-H, HCD + HSYA 100 μg/mL; PCA + HSYA-H, HCD + PCA 100 μg/mL + HSYA 100 μg/mL (A-B)Control, (C)HCD, (D)Sim, (E)PCA-H, (F)HSYA-H and (G)PCA + HSYA-H groups. Magnification: (A)100 × and (B–G)400 × .
Fig. 8
Fig. 8
Contents of SCFAs in zebrafish larvae. The Control group; HCD group; PCA-H, HCD + PCA 100 μg/mL; HSYA-H, HCD + HSYA 100 μg/mL; PCA + HSYA-H, HCD + PCA 100 μg/mL + HSYA 100 μg/mL (A)Acetic acid, (B)propionic acid, (C)butyric acid, (D)isobutyric acid, (E)valeric acid, (F)isovaleric acid and (G)caproic acid. *P < 0.05, in comparison with the HCD group, and the error bars represent SD.
Fig. 9
Fig. 9
Relative mRNA expression in zebrafish groups. The Control group; HCD group; PCA-H, HCD + PCA 100 μg/mL; HSYA-H, HCD + HSYA 100 μg/mL; PCA + HSYA-H, HCD + PCA 100 μg/mL + HSYA 100 μg/mL. Relative mRNA expression of SREBP2, SREBP1, AMPK, PCSK9, LDLR, HMGCR, PPAR-γ, C/EBPα, mTOR, HNF-1α and FoxO3a. ###P < 0.001, in comparison to the Control group. ***P < 0.001, in comparison to the HCD group.
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