Additional file 1: Table S1. of Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study

SNPs studied and their frequencies in our population. This table contains the description and frequencies of the SNP investigated in the study for ABCB1, UGT, MRP2, SLCO1B1 and SLCO1B2 genes. (DOCX 22 kb

Fasting plasma parameters in 12-wk wild type (WT) and HSL^+/− HFD-fed mice and in 12-wk wild type HFD-fed mice treated with vehicle or HSL specific inhibitor (HSLi) for 7 consecutive days.

<p>Values (<i>n</i> = 6–17) are means ± SEM. NEFA, nonesterified fatty acid; QUICKI, quantitative insulin sensitivity check index; RBP4, retinol binding protein 4.</p

In vivo fatty acid fluxes in HFD-fed HSL^+/− and WT mice.

<p>(A) Plasma parameters of fatty acid fluxes. (B) Rate of radiolabelled fatty acid incorporation in the TG pool of tissues. (C) Total TG content in tissues. Values are means ± SEM. WT mice (▪) (<i>n</i> = 5) and HSL^+/<b>−</b> mice (□) (<i>n</i> = 6). * <i>p</i><0.05, *** <i>p</i><0.001 versus WT mice.</p

Consequence of partial inhibition of WAT lipolysis on fatty acid and glucose metabolism and insulin sensitivity.

<p>Partial inhibition of lipolysis modifies FA flux with a decrease in WAT FA uptake concurring to maintenance of fat mass and an increase in glucose uptake that favours de novo lipogenesis, which may be a key player in the restoration of insulin sensitivity. DNL, de novo lipogenesis; FA, fatty acid; NEFA, nonesterified fatty acid; TG, triacylglycerol.</p

Fate of glucose and fatty acid in hMADS adipocytes.

<p>(A) HSL (LIPE) expression as mRNA (upper panel) and protein (lower panel). (B) Fatty acid oxidation. (C) Basal and insulin-stimulated glucose uptake. (D) Basal and insulin-stimulated glucose oxidation. (E–F) Basal and insulin-stimulated glucose carbon incorporation into glycerol (E) or fatty acid (F) of neutral lipids. hMADS adipocytes were transfected either with a siRNA against GFP (control; siGFP) or HSL (siHSL). Data are fold induction of siGFP values (means ± SEM). siGFP adipocytes (▪) and siHSL adipocytes (□) (<i>n</i> = 5–10). * <i>p</i><0.05, ** <i>p</i><0.01 versus siGFP.</p

Glucose metabolism and insulin sensitivity in mice with reduced HSL activity.

<p>(A) In vivo 2-deoxy-D-[³H] glucose uptake under stimulation by insulin in skeletal muscle (<i>biceps femoris</i>—BF—and <i>soleus</i>) and WAT. (B) Ex vivo glucose oxidation in <i>soleus</i> muscle. (C) Respiratory quotient assessed by indirect calorimetry and expressed as percentage of cumulative relative frequencies (PCRF). EC₅₀ are represented by arrows. (D) In vivo insulin bolus. Variation in plasma glucose 15 min after injection of saline or insulin (a.u., arbitrary unit). (E) Effect of insulin bolus in vivo on hepatic insulin signalling. IRS1, insulin receptor substrate 1; Akt, protein kinase B. (F) Hepatic de novo lipogenesis. Measurement of radiolabelled glucose incorporation in lipid fraction of liver after insulin stimulation. (G) Pyruvate tolerance test. (H) Liver glycogen content assessed in mice starved for 24 h and then refed for 18 h. Values are means ± SEM. WT mice (▪ or ▴) and HSL^+/− mice (□) mice (<i>n</i> = 4–10 in each group). * <i>p</i><0.05, ** <i>p</i><0.01 versus WT mice.</p

Relationship between WAT lipolysis and de novo lipogenesis.

<p>(A) Up-regulation of glucose transporter 4 and de novo lipogenesis-related pathways. Induction of gene expression (red boxes) in hMADS adipocytes with HSL gene silencing were determined by DNA microarray analysis and validated by reverse transcription-quantitative PCR (indicated by *). (B) Up-regulation of glucose transporter 4 and de novo lipogenesis-related pathway gene expression in hMADS adipocytes. mRNA levels were determined by reverse transcription-quantitative PCR (<i>n</i> = 9–12). ** <i>p</i><0.01 versus siGFP. (C) Correlations between glucose transporter 4, carbohydrate responsive element-binding protein, and fatty acid synthase mRNA levels and, lipolysis in human WAT (<i>n</i> = 45). (D) Up-regulation of glucose transporter 4 and de novo lipogenesis-related pathway gene expression in adipocytes from obese individuals treated with placebo or nicotinic acid (<i>n</i> = 12 per group). * <i>p</i><0.05, ** <i>p</i><0.01 versus before treatment. ACC, acetylCoA carboxylase; ACL, ATP citrate lyase; ACS, acetyl-CoA synthase; ChREBP, carbohydrate responsive element-binding protein; DCT, dicarboxylate transporter; FAE, fatty acid elongase; FAS, fatty acid synthase; GPDH, glycerol-3-phosphate dehydrogenase; GLUT4, glucose transporter 4; G6PDH, glucose-6-phosphate dehydrogenase; LDH, lactate dehydrogenase; MDH, malate dehydrogenase; ME, malic enzyme; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PK, pyruvate kinase; SCD, stearoylCoA desaturase.</p

WAT inflammation in 12-wk HFD-fed HSL^+/− and WT mice.

<p>(A) Macrophage (CD45/F480/CD11b triple positive cells) number per milligram of WAT assessed by flow cytometry. (B) mRNA expression of WAT macrophage surface markers. (C) mRNA expression of WAT inflammatory markers. Values are means ± SEM. WT mice (▪) (<i>n</i> = 7) and HSL^+/<b>−</b> mice (□) (<i>n</i> = 8).</p

WAT lipases and lipolysis in HFD-fed WT, HSL^+/−, and HSL^−/− mice.

<p>(A) mRNA expression of HSL (lipe), ATGL (pnpla2), CGI-58 (abhd5), and plin1 in epididymal WAT. (B–C) Western blot analysis of HSL (B) and ATGL (C) protein expression. (D–E) In vitro hydrolase activities against cholesterol ester (D) and TG (E) analogs in the absence and presence of HSL specific inhibitor. (F) In vitro basal and isoproterenol-stimulated (ISO) lipolysis in isolated adipocytes. (G) In vivo lipolysis expressed as fold increase over saline. Plasma glycerol levels were measured 15 min after saline or isoproterenol injection. Values are means ± SEM. WT mice (black bars) (<i>n</i> = 6–8); HSL^+/− mice (white bars) (<i>n</i> = 6–9); HSL^−/− mice (gray bars) (<i>n</i> = 4). * <i>p</i><0.05, ** <i>p</i><0.01, *** <i>p</i><0.001 versus WT mice; ^###<i>p</i><0.001 versus basal condition.</p

Relationship between WAT lipolytic capacities and insulin sensitivity in human subjects.

<p>(A) Simple linear regression between lipolysis and HOMA-IR (<i>n</i> = 367). (B) Simple linear regression between lipolysis and insulin tolerance (<i>n</i> = 126). (C) BMI and HOMA-IR before and 2 y after bariatric surgery (<i>n</i> = 25). (D) Correlation between variations in lipolysis and changes in HOMA-IR following bariatric surgery (<i>n</i> = 25).</p