Prof Stefano Fiorucci - Progress in lipid research
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1) The document describes several metabolic pathways involving cholesterol, bile acids, and steroid hormone synthesis. 2) It shows the neutral and acidic pathways for cholesterol catabolism into bile acids and the primary and secondary bile acid synthesis pathways. 3) Several figures are presented outlining the roles of nuclear receptors like FXR, LXR, PXR, and VDR in regulating bile acid, cholesterol, and triglyceride metabolism in the liver, intestine, and kidneys.
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Prof Stefano Fiorucci - Progress in lipid research
- 1. Androgen Acetyl-CoA Acetoacetyl-CoA Cholesterol pathways Estrogen Mineralcorticoids Cholesterol Glucocorticoids HMG-CoA synthase HMG-CoA pregnenolone PXR HMG-CoA reductase 5β-pregnenolone- 3,20dione Neutral pathway Acidic pathway CYP7A1 CYP27A1 7α-deydrocholesterol Vitamin D3 27-hydrocholesterol oxysterols CYP27A1 CYP7B1 VDR Primary BAs Secondary BAs LXR FXR CDCA LCA CYP8B1 DCA CA Figure 1
- 2. Bile acids FXR VDR Systemic circulation Mrp3 PXR CAR Ntcp Portal vein Phase II Oatp-1 Phase I Mrp4 Ugt2b4/7 Ugt1a1 Sult2a1 Cyp3a4 Ostα/β BA-OH BA-GlcA BA-GlcA BA-SO BSEP Mrp3 Mrp2 Bile canalicular efflux Renal BA excretion Figure 2 Fecal BA excretion
- 3. Decrease LDL plasmatic LDLr levels expression CAR Cyp39A1 HMGCoA reductase FXR PXR Cholesterol Cholesterol catabolism ApoA1 synthesis ApoA1 PCSK9 SR-B1 SR-B1 ABCA1 HDL LDLr Increase HDL HDL Decrese HDL synthesis activity clearance synthesis clearance Decrease Decrease LDL/HDL plasmatic HDL plasmatic human levels levels A mouse B Figure 3
- 4. FAS Triglyceride activity synthesis CAR PXR FXR PPARα Srebp-1c β-Oxidation PPARα CTP-1 ApoC III CD36 VLDL Fas ApoA V Acc-1 β-Oxidation receptor ApoC II Scd-1 Syndecan-1 human lipogenesis Increase LPL mouse activity A Increase VLDL and CM B clearance Figure 4
- 5. hyperglicaemia FXR Insulin resistance GS GLUT4 G6Pase PK PEPCK glycogen synthesis Insulin F1,6bPase glycolisis signaling FAs synthesis Inflammatory cytokines SKELETAL MUSCLE gluconegenesis Glucose production Glucose uptake LIVER appetite Insulin secretion FXR Adipocytes β cells protection GLUT4 differentiation Lipid GLP-1 GLP-1 TGR5 Inflammatory storage cytokines AC GDP WAT αβ γ P PANCREAS c-AM GTP α Figure 5 GUT
- 6. Agonists CAR PXR PGC-1α CREB FoxO1 HNF4α PEPCK G6Pase gluconeogenesis Figure 6
- 7. Skeletal muscle TGR5 AC T4 TR T3 D2 1α C-AMP PGC 2 P α β γ UCP FXR GD P CRE GT α Rα PK PPA Uncoupling n FFA / atio TRIGLYCERIDES B-oxidation xid Β-o Oxidative phosphorylation large adipocyte TNF-α IR T4 TR AC T3 TGR5 P D2 C1 PG P1 α c-AM UC FXR adiponectin P2 /3 γ UC αβ DP G CRE adipocytes differentiation leptin P GT α CAR BAT WAT pre-adipocyte Figure 7