Targets of statins intervention in LDL-C metabolism: Gut microbiota

Abstract

Increasing researches have considered gut microbiota as a new "metabolic organ," which mediates the occurrence and development of metabolic diseases. In addition, the liver is an important organ of lipid metabolism, and abnormal lipid metabolism can cause the elevation of blood lipids. Among them, elevated low-density lipoprotein cholesterol (LDL-C) is related with ectopic lipid deposition and metabolic diseases, and statins are widely used to lower LDL-C. In recent years, the gut microbiota has been shown to mediate statins efficacy, both in animals and humans. The effect of statins on microbiota abundance has been deeply explored, and the pathways through which statins reduce the LDL-C levels by affecting the abundance of microbiota have gradually been explored. In this review, we discussed the interaction between gut microbiota and cholesterol metabolism, especially the cholesterol-lowering effect of statins mediated by gut microbiota, via AMPK-PPARγ-SREBP1C/2, FXR and PXR-related, and LPS-TLR4-Myd88 pathways, which may help to explain the individual differences in statins efficacy.

Keywords: cholesterol metabolism; gut microbiota; low density lipid cholesterol; potential pathways; statins.

Figure 1

Microbiota-driven, LDL-lowering effect of statins. Atorvastatin, simvastatin and rosuvastatin enter the intestine via the upper gastrointestinal tract through oral administration and affect the absolute and relative abundance of gut microbiota, which in turn affects SCFAs, SBAs, TMA, LPS and other MDMs. The MDMs are transported to the liver through the portal venous system, ultimately achieving the purpose of regulating cholesterol metabolism and LDL-C levels. LPS, lipopolysaccharides; MDMs, microbiota-derived metabolites; LDL-C, low-density lipoprotein cholesterol; SBAs, secondary bile acid; SCFAs, short-chain fatty acid; TMA, trimethylamine.

Figure 2

Statins-related microbiota metabolism and pathways in cholesterol metabolisms. In cholesterol metabolism, changes in gut microbiota composition and its metabolites are markers for regulating the gut-liver axis and can reflect the effect of statins. The liver-gut axis can be used as one of the ways statins affect cholesterol metabolism and can explain the why the efficacy of statins differs individually. SCFAs, SBAs, TMA, LPS, and other MDMs are changed after statins administration. SCFAs and SBAs can activate enterocytes to secrete FGF19 and GLP-1 into the blood, and others are absorbed by enterocytes into the blood circulation and finally absorbed in the liver through the portal vein system. This affects the AMPK-PPARγ-SREBP1C/2, FXR and TGR5 signaling pathways and LPS-TLR4-Myd88 and PI3K-Akt in hepatocytes to promote BAs excretion, reduce cholesterol synthesis and promote cholesterol consumption. AMPK, AMP-activated protein kinase; CYP7A1, cytochrome p-450 enzyme cholesterol 7α-hydroxylase; CYP27A1, cytochrome p-450 enzyme cholesterol 27α-hydroxylase; FXR, farnesoid X receptor; FGF 19, fibroblast growth factor 19; FGFR4, fibroblast growth factor receptor 4; GLP-1, glucagon-like peptide 1; GLP-1R, GLP-1 receptor; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; LPS, lipopolysaccharides; MAPK, mitogen-activated protein kinases; MDMs, microbiota-derived metabolites; Myd88, myeloid differentiation factor 88; PI3K-Akt, the phosphatidylinositol-3-kinase; PPAR, peroxisome proliferator-activated receptor γ; SBAs, secondary bile acid; SCAP, SREBP cleavage-activating protein; SCFAs, short-chain fatty acid; SHP, FXR-small heterodimer partner; SREBP, sterol regulatory element binding protein; TGR5, cell surface receptor G protein-coupled bile acid receptor 5; TLR4, Toll-like receptor 4; TMA, trimethylamine; TMAO, trimethylamine-N-oxide.