Laparoscopic sleeve gastrectomy modifies cholesterol synthesis but not cholesterol absorption

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Obesity Research & Clinical Practice (2016) xxx, xxx—xxx

RESEARCH LETTER

Laparoscopic sleeve gastrectomy modifies cholesterol synthesis but not cholesterol absorption KEYWORDS Morbid obesity; Sleeve gastrectomy; Cholesterol synthesis; Cholesterol absorption; Non cholesterol sterols; Bariatric surgery

Summary Background and aims: Each bariatric surgery procedure impacts differently on cholesterol synthesis and absorption. Although a restrictive procedure, sleeve gastrectomy resolves diabetes mellitus and, like mixed-type procedures, induces early changes in gastrointestinal hormones. To our knowledge the present study is the first to assess the effects of sleeve gastrectomy on cholesterol synthesis and absorption. Methods and results: 42 consecutive subjects with obesity and sleeve gastrectomy candidates were included in the study together with a control group of 20 subjects without obesity. Before sleeve gastrectomy and 10 months afterwards, all subjects underwent a clinical examination, blood tests, ultrasound visceral fat area estimation and determination of plasma lathosterol, campesterol and sitosterol concentrations. After sleeve gastrectomy, significant decreases were observed in BMI, waist circumference, visceral and subcutaneous fat, blood pressure, triglycerides, insulin and glucose levels, lathosterol and HOMA-IR. HDL-C and apolipoprotein AI levels increased significantly. No significant differences emerged in LDL-C, apolipoprotein B levels or cholesterol absorption markers. Lathosterol levels correlated significantly with BMI, visceral fat area and HOMA-IR. Differences in cholesterol intake after surgery were not significantly associated with differences in lathosterol, campesterol and sitosterol concentrations. Conclusions: Sleeve gastrectomy reduced the markers of cholesterol synthesis but did not modify cholesterol absorption. Changes in cholesterol synthesis and absorption were independent of variations in cholesterol intake, suggesting a specific sleeve gastrectomy-related effect. © 2016 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Introduction The rising prevalence of morbid obesity [1] bolstered the demand for bariatric or ‘‘metabolic’’ surgery which seems to be more effective than conventional therapies.

Each bariatric surgery procedure, besides improving lipid profile [2,3], can impact differently on non-cholesterol sterols, currently used to estimate cholesterol synthesis and absorption and also useful markers of lipid absorption. Gastric banding reduces cholesterol synthesis and increases cholesterol absorption [4]; the Roux-en-Y gastric bypass

http://dx.doi.org/10.1016/j.orcp.2016.12.004 1871-403X/© 2016 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: De Vuono S, et al. Laparoscopic sleeve gastrectomy modifies cholesterol synthesis but not cholesterol absorption. Obes Res Clin Pract (2016), http://dx.doi.org/10.1016/j.orcp.2016.12.004

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Research Letter

Figure 1 Intake modifications before and after sleeve gastrectomy. SAFA: saturated fatty acids MUFA: monounsaturated fatty acids PUFA: polyunsaturated fatty acid Table 1

Characteristics of the population before surgery.

Age (years) SBP (mmHg) DBP (mmHg) Weight (kg) BMI (kg/m2 ) Waist circumference (cm) VFA (cm2 ) Subcutaneous fat (cm) Triglycerides (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) Glycemia (mg/dl) Insulinemia (␮IU/ml) HOMA-IR Apolipoprotein AI (mg/dl) Apolipoprotein B (mg/dl) Lathosterol (␮mol/mmol) Campesterol (␮mol/mmol) Sitosterol (␮mol/mmol)

Obese (n.42)

Controls (n.20)

p

45 ± 13 138 ± 16 84 ± 8 122 ± 27 44 ± 7 130 ± 18 249 ± 74 28 ± 8 146 ± 107 50 ± 14 117 ± 35 102 ± 33 18 ± 16 4.7 ± 4.1 133 ± 25 98 ± 23 194 (151—270) 49 (28—71) 45 (25—71)

54 ± 16 126 ± 10 80 ± 6 68 ± 7 25 ± 2 90 ± 8 152 ± 36 15 ± 6 138 ± 46 48 ± 15 127 ± 23 87 ± 7 6±5 1.4 ± 1.3 163 ± 27 107 ± 21 76 (57—95) 54 (27—95) 83 (63—116)

0.026 0.001 ns <0.001 <0.001 <0.001 <0.001 <0.001 ns ns ns ns <0.001 <0.001 <0.001 ns <0.001 ns <0.001

SBP = systolic blood pressure; DBP = diastolic blood pressure; BMI = body mass index. VFA = visceral fat area; HOMA-IR = HOmeostasis Model Assessment of Insulin Resistance.

decreases cholesterol synthesis and absorption [4]; after biliopancreatic diversion, cholesterol absorption drops while cholesterol synthesis rises [3]. To our knowledge no studies have, as yet, evaluated cholesterol synthesis/absorption patterns after laparoscopic sleeve gastrectomy (LSG). LSG provides significant weight loss, similar early changes in gastrointestinal hormones as mixed-type procedures and marked improvements in, or remission of, co-morbidities like diabetes mellitus [5,6]. Sleeve gastrectomy is also effective in reducing the prevalence of the metabolic syndrome was well documented by Péquignot et al. [7]. The present study evaluated cholesterol synthesis and absorption modifications in subjects with

morbid obesity before and after sleeve gastrectomy.

Subjects, materials and methods We retrospectively enrolled 42 subjects with obesity (13 males, 29 females), referred to Perugia University Internal Medicine Unit, from November 2011 to December 2013 for cardiovascular and metabolic assessment, one month before and ten months after sleeve gastrectomy. A control group of 20 subjects without obesity (10 males and 10 females) was also included in the study. Data were collected on computer database.

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Figure 2 Univariate correlations. BMI: body mass index VFA: visceral fat area HOMA-IR: HOmeostasis Model Assessment of Insulin Resistance

All subjects underwent a clinical examination, which included BMI evaluation and waist circumference and blood pressure measurement. The following laboratory parameters were determined: complete lipid profile, plasma glucose, serum insulin, glycated haemoglobin (HbA1c), HOmeostasis Model Assessment of Insulin Resistance (HOMA-IR), apolipoprotein AI and B. Plasma lathosterol, campesterol and sitosterol levels were measured by gas chromatography coupled to mass spectrometry (GC—MS) with multiple selected ion monitoring according to Ahmida et al. [8]. Non-cholesterol sterols were standardised and expressed as cholesterol ratios (102 ␮mol/mmol cholesterol). Before surgery and 10 months afterwards, a questionnaire on dietary history was administered to 15/42 patients with obesity in order to quantify ingested calories (Kcal), carbohydrates (g/die), proteins (g/die), saturated, monounsaturated, polyunsaturated fats (g/die) and daily cholesterol (mg/die). Visceral fat area was measured by ultrasonography as described by Hirooka et al. [9]. All the assessments well carried by the same operator and the intra-operator inter-day coefficient of variation was 1.8%. We used Student’s t test and the Mann—Whitney U test to compare parametric and non-parametric variables between subjects with obesity and controls. For comparing pre- and post-surgery parametric and non-parametric variables we used the paired t-test and Wilcoxon test. Spearman’s rank correlation coefficients tested the relation between the variables. Analyses were performed with SPSS software (version 17.0; SPSS, Inc., Chicago, IL), with statistical significance set at p < 0.05.

Results Table 1 shows demographics and clinical features of subjects with obesity and controls. Before surgery five obese were diabetic, only one on glucoselowering therapy; three obese were dyslipidemic and assumed lipid lowering medications. Lathosterol levels were significantly higher in patients with obesity while sitosterol levels were significantly lower; campesterol levels did not differ significantly in the two groups. As shown in Table 2 after surgery we observed significant drops in BMI, waist circumference, visceral and subcutaneous fat, systolic and diastolic blood pressure, triglycerides, glycemia, serum insulin and HOMA index. Apoprotein AI and HDLC levels increased significantly. Lathosterol levels decreased significantly, while cholesterol absorption markers were not significantly modified. After surgery we observed diabetes remission in all diabetic subjects; only one dyslipidemic subject continued to assume lipid lowering medications. Lipid and calorie intake patterns before and after sleeve gastrectomy are shown in Fig. 1. In univariate correlation analysis lathosterol showed a significant positive correlation with BMI, visceral fat area and HOMA-IR (Fig. 2). After surgery differences in cholesterol intake () were not significantly associated with differences in lathosterol, campesterol and sitosterol () concentrations.

Discussion The present study confirms that severe obesity is closely associated with the metabolic features

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Research Letter Table 2

Characteristics of obese subjects before and after sleeve gastrectomy.

SBP (mmHg) DBP (mmHg) Weight (kg) BMI (kg/m2 ) Waist circumference (cm) VFA (cm2 ) Subcutaneous fat (cm) Triglycerides (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) Glycemia (mg/dl) Insulinemia (␮IU/ml) HOMA-IR Apolipoprotein AI (mg/dl) Apolipoprotein B (mg/dl) Lathosterol (␮mol/mmol) Campesterol (␮mol/mmol) Sitosterol (␮mol/mmol)

Before

After

p

138 ± 16 84 ± 8 122 ± 27 44 ± 7 130 ± 18 245 ± 74 28 ± 8 146 ± 107 50 ± 14 117 ± 35 102 ± 34 17 ± 15 3.9 ± 2.7 131 ± 26 98 ± 22 194 (151—270) 49 (28—71) 45 (25—71)

124 ± 15 75 ± 10 90 ± 19 32 ± 5 105 ± 15 142 ± 43 18 ± 5 111 ± 52 55 ± 14 118 ± 27 81 ± 10 7±4 1.6 ± 1.2 146 ± 22 96 ± 20 103 (63—136) 37 (22—59) 38 (27—62)

0.001 0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.006 0.016 ns <0.001 <0.001 <0.001 <0.001 ns <0.001 ns ns

SBP = systolic blood pressure; DBP = diastolic blood pressure; BMI = body mass index. VFA = visceral fat area; HOMA-IR = HOmeostasis Model Assessment of Insulin Resistance.

of insulin-resistance and that insulin-resistance is associated with high cholesterol synthesis and low cholesterol absorption [10]. The present study is the first to assess cholesterol synthesis and absorption modifications after LSG. The main finding was that, besides reducing BMI and improving insulin-resistance, LSG reduced cholesterol synthesis. Although often included among restrictive procedures LSG is not comparable to gastric banding because it removes about 80% of the stomach. The LSG-induced drop in cholesterol synthesis could be due to insulin-resistance correction, as has been observed after mixed-type bariatric surgery procedures. The decrease in cholesterol synthesis was not associated with a compensatory rise in cholesterol absorption, probably because removal of most of the stomach, causes cholecystokinin production to drop and thus reduce cholesterol absorption [3]. In our view LSG should not be considered merely a restrictive procedure, as its beneficial effects are similar to those of the Roux-en-Y gastric bypass, even though it impacts less on malabsorption. The LSG-specific effects on cholesterol synthesis and absorption markers appeared to be independent of variations in cholesterol intake as differences () after surgery were not significantly associated with differences in lathosterol, campesterol and sitosterol () concentrations. In conclusion, LSG significantly reduced cholesterol synthesis but did not impact significantly on cholesterol absorption. These modifications seem

to be independent of variations in cholesterol intake. Whether gastric volume restriction was the only factor determining these benefits is still unclear and further studies are needed.

Declaration of conflicting interests We state that the article is original, has not been previously published in any form and is not being considered for publication elsewhere in whole or in part. All authors have read and approved the manuscript and have contributed substantially to the conception and completion of the review and to paper draft. None of the authors has financial or other conflicts of interest that might have biased the work.

Ethical approval The protocol was approved by the Ethic Committee of our Institution. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent Written informed consent was obtained from each study participant.

Acknowledgement We thank Dr Geraldine Anne Boyd, lecturer in Scientific English at the faculty of medicine, University of Perugia, for the English language and style correction of this paper.

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S. De Vuono ∗ M.A. Ricci D. Siepi Internal Medicine, Department of Medicine, University of Perugia, Italy M. Boni Surgery Department, San Giovanni Battista Hospital, Foligno, Italy A. Gentili M. Scavizzi G. Daviddi P. Labate A.R. Roscini G. Lupattelli Internal Medicine, Department of Medicine, University of Perugia, Italy ∗ Corresponding

author at: Internal Medicine, ‘‘Santa Maria della Misericordia’’ Hospital, University of Perugia, Department of Medicine, Piazzale Lucio Severi, Sant’Andrea delle Fratte, 06132 Perugia, Italy. Fax: +39 075 5784022. E-mail addresses: [email protected] (S. De Vuono), [email protected] (M.A. Ricci), [email protected] (D. Siepi), [email protected] (M. Boni), [email protected] (A. Gentili), [email protected] (M. Scavizzi), [email protected] (G. Daviddi), [email protected] (P. Labate), [email protected] (A.R. Roscini), [email protected] (G. Lupattelli). 31 August 2016

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Please cite this article in press as: De Vuono S, et al. Laparoscopic sleeve gastrectomy modifies cholesterol synthesis but not cholesterol absorption. Obes Res Clin Pract (2016), http://dx.doi.org/10.1016/j.orcp.2016.12.004