Table 2.

Summarised anti-atherosclerotic and hypolipidemic effects of alkaloids included in the review through PPARs, LXRs, PCSK9, and inflammatory markers modulation.

Alkaloids
Compound	Main natural source	Biological activity	References
Tetramethylpyrazine	Ligusticum chuanxiong	Amelioration of lipid metabolism, inflammatory and oxidant markers in animal models.	[[93], [94], [95], [96]]
		Increase of PPARs, LXRs and ABCA1 expression in hepatoma cells.
		Amelioration of vascular calcification via PPARγ activation in VSMC cells.
		Decrease of TLR4 and NF-kB expression in HUVEC cells and in mice.
Berberine	Rhizoma coptidis, Berberis L.	Reduction of total and LDL-C in clinical trials.	[26,[97], [98], [99], [100], [101], [102], [103], [104], [105]]
		Reduction of cholesterol uptake in macrophages.
		Activation of PPARα and γ with improvement of lipid metabolism in hypercholesterolemic mice.
		Amelioration of atherosclerosis and increase in PPARγ in ApoE−/− mice.
		Suppression of PCSK9 in HepG2 cells and in dyslipidemic subjects.
		Reduction of plasma cholesterol, LDL-C, triglycerides in a mouse model of atherosclerosis.
		Downregulation of NF-kB pathway and decrease of pro-inflammatory cytokines in HUVEC cells.
		Decrease the expression of ICAM-1, reduce inflammation and atherosclerosis.
Caffeine	Coffea arabica L. and canephora Pierre ex A.Froehner, Camellia sinensis (L.) Kuntz	Inhibition of SREBP-2, PCSK9 and increase in LDLR in healthy volunteers and in hepatocytes models.	[67,106,107]
		Decrease in lipid droplet, adipogenesis and oxidative stress via PPARγ in a model of Graves' orbitopathy.
		Reduction of CRP and cytokines secretion and lipid peroxidation in clinical trials.
Theobromine	Theobroma cacao L.	Downregulation of SREBP-1c, FAS, CD36, FABP4, PPARα, CPT1 in vitro and in vivo.	[108]

Abbreviations: ABCA1, ATP-binding cassette transporter genes A1; CD36, cluster of differentiation 36; CPT-1, carnitine palmitoyltransferase; CRP, C-reactive protein; FABP4, fatty acid binding protein 4; FAS, fatty acid synthase; ICAM-1, intracellular adhesion molecule 1; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; LXR, liver X receptor; NF-kB, nuclear factor kappa B; PCSK9, proprotein convertase subtilisin/kexin type 9; PPAR, peroxisome proliferator-activated receptor; SREBP, sterol regulatory element-binding protein; TLR4, toll-like receptor 4.