Table 1: Dietary Fructose in the Pathogenesis of NAFLD and CKD

ONLINE SUPPLEMENTARY MATERIAL

Table 1: dietary fructose in the pathogenesis of NAFLD and CKD

Dietary fructose
Cellular mechanism / Biological effect / Therapeutic opportunities
Pancreatic β-cell[22-24]:
absent postprandial insulin response
Adipocyte:
absent postprandial leptin response
Hypothalamus:
­dopamine tone
Hepatocyte, skeletal miocyte:
↓ fat oxidation and REE
Hepatocyt[22-3]: e:
­ fructokinase-mediated ATP depletionà­ AMPD-2à↓ AMP levelsà­ uric acid synthesis
Hepatocyte, adipocyte, renal endothelial and tubule cell[24-27]: s:
uric acid à↓ AMPK activityà ↓ FFA oxidation
uric acidà­ PERK and IRE1-α phosphorylation and XBP-1 splicing àER stressà­ SREBP-1cà­ de novo lipogenesis
uric acid à NOX activationà­ ROS generationà
1)mitochondrial dysfunction
2) citrate release in the citosolà­ de novo lipogenesis
3)NLRP3 inflammasome activattionà­ IL-1, TNFa,
SOCS-3 secretion
4) ↓ adiponectin secretion / ­ appetite and calorie intake
↓ calorie expenditure
Liver:
­ steatosis and necroinflammation
Adipose tissue:
adipose tissue dysfunction
Kidney:
↓ NO bioavailability
àendothelial dysfunction, glomerular and tubular inflammation and fibrosis
Insulin resistance / Dietary restriction of soft-drink beverages and sugar-sweeteners
Xantine oxidase inhibitors (allopurinol, febuxostat),
uricosuric agents (benzbromarone

Abbreviations: AMP: adenosine-monophosphate; AMPD: AMP deaminase; AMPK: adenosine-monophosphate kinase; ATP: adenosine triphosphate; COX: ciclo-oxygenase; EMT: epithelial-to-mesenchymal transition; CYP: cytochrome protein; ER: endoplasmic reticulum; ERK: extracellular signal-regulated kinase;; FFA: free fatty acids; FXR: farnesoid X-receptor; HSC: hepatic stellate cell; IL: interleukin; IRE1α: inositol requiring-1α; IRS-1: insulin receptor substrate-1; LPS: lipopolysaccharide; MCP-1: monocyte chemotactic protein-1; nAChR: nicotinic acetylcholine receptor; NF-kB: nuclear factor-kB; NLRP3: NOD-like receptor superfamily, pyrin domain containing 3; NO: nitric oxide; NOX: NADPH oxidase; PERK: protein kinase RNA-activated-like ER kinase; PPAR: peroxisome proliferators-activated receptor; RAS: rennin-angiotensin system; REE: resting energy expenditure; ROS: reactive oxygen species; SHP: small heterodimer partner; SMAD. small mother against decapentaplegic; SOCS-3: suppressor of cytokine signaling 3; SREBP: sterol-responsive element binding protein; STAT3: signal transducer and activator of transcription-3; TGF-β: transforming growth factor- β; TLR: toll-like receptor; TNF: tumor necrosis factor; VDR; vitamin D receptor; XBP-1: X-box-binding protein-1.

Table 2: role of hepatokines and of dysregulated cholesterol metabolism in the pathogenesis of CKD

Fibroblast Growth Factor-21 (FGF-21)
Cellular mechanism / Biological effect / Therapeutic options
Hepatocyte[65, 68-70]
­MAPK)-1 and MAPK-2 phosphorylationà­Akt phosphorylationà­ insulin signalling
¯ gluconeogenesis (insulin-mediated)
­ gluconeogenesis(FGF21-mediated)
­AMPK-SIRT1-PGC-1α activationà­ mitochondrial biogenesis and functionà­ fatty acid oxidation
¯ SREBP-1c expression௠de nvo lipogenesis
¯ eIF2α-ATF4-CHOP activationàER stress / ­ insulin sensitivity(
¯ glycemia
¯ liver fat / PEG-FGF21, remombinant FGF21, antiFGFR1 mAb
Adipocyte[68-70]
­GLUT1 expression
­MAPK)-1 and MAPK-2 phosphorylationà­Akt phosphorylationà­ insulin signalling
­AMPK-SIRT1-PGC-1α activationà­ mitochondrial biogenesis and functionà­ fatty acid oxidation
­Uncoupling Protein 1 (UCP1)à­ thermogenesis
¯ SREBP-1c expression௠de nvo lipogenesis
­ adiponectin secretion / ­ insulin sensitivity
¯ glycaemia
¯ adipose tissue
Skeletal miocyte[65, 68-70]
­AMPK-SIRT1-PGC-1α activationà­ mitochondrial biogenesis and functionà­ fatty acid oxidation
­Uncoupling Protein 1 (UCP1)à­ thermogenesis / ­ insulin sensitivity
¯ glycaemia
Hypothalamus[68-70]
­ hepatic insulin sensitivity(
¯ gluconeogenesis (insulin-mediated)
Pancreas[65]
¯ β-cell apoptosis
­ glucose-induced insulin secretion and β-cell function / ¯ glycaemia
Mesangial cells, podocytes, tubule cells[72-73]:
­MAPK)-1 and MAPK-2 phosphorylationà­Akt phosphorylationà­ insulin signalling
¯ SREBP-1c expression௠de nvo lipogenesis
¯ HMG-CoAR and ACC௠cholesterol synthesis
­ ABCA1 expression
¯ lipperoxidation௠ROS production
¯ mesangial expansion and TGF-β secretion
¯ tubular cell apoptosis
¯ NF-kB activation௠pro-inflammatory cytokine secretion / ¯ renal cholesterol and triglyceride accumulation
¯ glomerulosclerosis and proteinuria
¯ tubulointerstitial inflammation and fibrosis
Fetuin-A
Cellular mechanism / Biological effect / Therapeutic implications
Hepatocyte, miocyte[83-85]
↓ tyrosine kinase and IRS-1 autophosphorylationà↓ insulin receptor tyrosine kinase activity / Hepatic and muscle insulin resistance / CNX-010-(11β-HSD1 inhibitor)
Adipocyte[83]
↓ adiponectin secretion
↑ circulating FFA-TLR-4 bindingà↑ proinflammatory adipokine secretion / Adipose tissue dysfuntion
Kidney[86]:
Complexation with calcium and phosphate to form stable colloidal mineral-protein spheres (CPPs)à­CPPs uptake by macrophages and endothelial SR-A1 / Vascular inflammation Endothelial dysfunction
Insulin-like growth factor (IGF)-1
Cellular mechanism / Biological effect / Therapeutic implications
Preglomerular vessels[92-94]
(mediated by IGF-1-receptor related tyrosine kinase/PI3K pathway activation)
↑synthesis of NO and vasodilatatory prostaglandins
↓ efferent arteriolar resistance
Podocyte
↓ apoptosis
↑ function / Normal glomerular flow
Normal glomerular barrier functionà↓ proteinuria / IGF-1 analogues
Sterol Regulatory Binding Protein(SREBP)-2
Cellular mechanism / Biological effect / Therapeutic implications
Hepatocytes, glomerular and proximal tubular epithelial cells[101, 103-106]:
­ HMGCRà­ cholesterol synthesis
LDL-R/CD36/SR-A1 up-regulationà­ cholesterol-rich lipoprotein uptake
¯ SR-B1 and ABCA1 transporters௠cellular cholesterol efflux / Cholesterol overload à
Necro-inflammation and fibrosis / No knowa SREBP-2 antagonist
Hepatocytes[101, 102]
¯ CYP7A1௠synthesis of bile acids CA and CDCA
¯ CYP27A1௠synthesis of bile acid CDCA / ¯ FXR activation by bile acids
Farnesoid X receptor (FXR)
Cellular mechanism / Biological effect / Therapeutic implications
Hepatocytes, renal glomeruli, mesangial and tubular cells[103, 106]
↓ SREBP-1c-mediated lipogenesis
­ PPAR-α-mediated FFA β-oxidation / ↓ lipid accumulation / FXR agonists (OCA)
Hepatocyte[101]
¯ hepatic gluconeogenesis
­ IRS-1 phosphorylation
¯ ApoC-III and apoA-1 synthesis
­ ApoC-II synthesis
­CYP7A1 and ABCG5/G810 expression / ¯ synthesis of HDL-C
­ clearance of VLDL
­ bile acid synthesis and cholesterol excretion into bile
Renal macrophage, Kupffer cell[101, 103-106]
↓ IkB-α phpsphorylationà↓ NF-kB activation
↓ monocyte chemotatic protein(MCP)1
­ KLF-2/KLF-4 expression
↓ TGF-ß secretion / ↓ inflammation
↓ fibrogenesis
hepatic stellate cell,, renal myofibroblast[101-103]:
↓ expression of TGF-ß-receptor / ↓ fibrogenesis
Podocytes[103-106]
↓ apoptosis
­podocin and synaptopodin expression / ­ glomerular barrier functionà↓ proteinuria
Mesangial cells: [103-106]
↓ NADPH oxidase(Nox)
­MnSOD expression
↓ mesangial expansion / ↓ oxidative stress
↓ glomerulosclerosis
Adipocyte[101, 102]:
­PPAR-g expression and AdipoQ expression
↓ TNF-a secretion / ↓ adipose tissue dysfunction

Abbreviations: ABCA1: ATP-binding cassette transporters A1; ACC: acetyl-CoA carboxylase;

ALDH3A1 Aldehyde dehydrogenase 3A1Cat: Catalase; CDDO: 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oicacid; DMF: dimethylfumarate,Glt-Px: Glutathione peroxidase; Glt-R: Glutathione reductase ; G6PD: Glucose-6-phosphate 1-dehydrogenase; HO-1: Heme oxygenase-1; TXN-R: GST: Glutathione S-transferase, Thioredoxin reductase; SOD Superoxide dismutase; EPHX1 Microsomal epoxide hydrolase 1 MGST: Microsomal glutathione S-transferase, NK-252: (1-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)-3-(pyridin-2-ylmethyl)urea).NQO1 NAD(P)H:quinone oxidoreductase; PSMB5: Proteasome 26S PSMB5 subunit; tBHQ: tert-Butylhydroquinone; UbC Ubiquitin C; : UGT: UDP glucuronosyltransferase; AICAR: 5-Aminoimidazole-4-carboxamide-1-β-D- ribonucleoside; AMPK: adenosine-monophosphate kinase; CA: cholic acid; CDCA. chenodeoxycholic acid; CD36: cluster of differentiation-36; CHOP: C/EBP homologous protein; CPP: calciprotein particles; CPT-1: carnitine palmitoyltransferase-I; ; ER: endoplasmic reticulum; FAS: fatty acid synthase; FFA: free fatty acids; FXR: farnesoid X-receptor; GLUT: glucose transporter; HMG-CoAR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase; IL: interleukin; 11β-HSD1: 11β-hydroxysteroid dehydrogenase type 1; IRS-1: insulin receptor substrate-1; KLF: Kruppel-like factor; LDL: low-density lipoprotein; LDL-R: low-density lipoprotein receptor; MCP-1: monocyte chemotactic protein-1; NO: nitric oxide; NOX: NADPH oxidase; OCA: obeticholic acid; PGC-1α: peroxisome proliferator-activated receptor-γ coactivator-1 α; ROS: reactive oxygen species; SCD-1: stearoyl-CoA desaturase-1; SR-A1: scavenger receptor-A1; SR-B1: scavenger receptor-B1; SREBP: sterol-responsive element binding protein; TGF-β: transforming growth factor- β; TLR: toll-like receptor; TNF: tumor necrosis factor; TZD: thiazolidinediones; VLDL: very low density lipoprotein; VSCMs: vascular smooth muscle cells;