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Acute Caloric Restriction Counteracts Hepatic Bile Acid and Cholesterol Deficiency in Morbid Obesity

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Acute Caloric Restriction Counteracts Hepatic Bile Acid and Cholesterol Deficiency in Morbid Obesity Original Article doi: 10.1111/joim.12599 Acute caloric restriction counteracts hepatic bile acid and cholesterol deficiency in morbid obesity S. Straniero1, F. Rosqvist2, D. Edholm3, H. Ahlstr€om4, J. Kullberg4, M. Sundbom3, U. Riserus2 & M. Rudling1 From the 1Department of Medicine, Karolinska University Hospital at Huddinge, Huddinge, Stockholm; 2Department of Public Health and Caring Sciences and Clinical Nutrition and Metabolism; 3Department of Surgical Sciences; and 4Department of Radiology, Uppsala University, Uppsala, Sweden Abstract. Straniero S, Rosqvist F, Edholm D, tein convertase subtilisin/kexin type 9 (PCSK9), Ahlstrom€ H, Kullberg J, Sundbom M, Riserus U, insulin, glucose and FGF19 were monitored. Fifty- Rudling M (Karolinska University Hospital at Hud four nonobese women (BMI <25 kg mÀ2) served as dinge, Huddinge, Stockholm; Uppsala University, controls. Uppsala, Sweden). Acute caloric restriction counteracts hepatic bile acid and cholesterol Results. At baseline, synthesis of both BAs and deficiency in morbid obesity. J Intern Med 2017; cholesterol and serum levels of BAs and PCSK9 281: 507–517. were elevated in the obese group compared to controls. Already after 3 days on a low-calorie Background. Bile acid (BA) synthesis is regulated by diet, BA and cholesterol synthesis and serum BA BA signalling in the liver and by fibroblast growth and PCSK9 levels normalized, whereas LDL factor 19 (FGF19), synthesized and released from cholesterol increased. FGF19 and triglyceride the intestine. In morbid obesity, faecal excretion levels were unchanged, and liver volume was and hepatic synthesis of BAs and cholesterol are reduced by 10%. strongly induced and caloric restriction reduces their faecal excretion considerably. We hypothe- Conclusions. The results suggest that hepatic BAs and sized that the high intestinal food mass in cholesterol are deficient in morbid obesity. Caloric morbidly obese subjects promotes faecal restriction rapidly counteracts these deficiencies, excretion of BAs and cholesterol, thereby creating normalizing BA and cholesterol synthesis and a shortage of both BAs and cholesterol in the circulating PCSK9 levels, indicating that overpro- liver. duction of cholesterol in enlarged peripheral tis- sues cannot explain this phenotype. We propose Methods. Ten morbidly obese women (BMI 42 Æ that excessive food intake promotes faecal loss of À 2.6 kg m 2) were monitored on days 0, 3, 7, 14 BAs and cholesterol contributing to their hepatic and 28 after beginning a low-calorie diet (800– deficiencies. 1100 kcal dayÀ1). Serum was collected and liver size and fat content determined. Synthesis of BAs Keywords: bile acid synthesis, cholesterol and cholesterol was evaluated from serum markers, synthesis, proprotein convertase subtilisin/kexin and the serum levels of lipoproteins, BAs, propro- type 9. Intestinal food contents bind BAs, promoting their Introduction faecal loss, which in turn is compensated for The prevalence of obesity is increasing globally to through induced BA synthesis. reach epidemic levels. Although the causes for this increase are multifactorial, a key factor is excessive The synthesis of BAs and the synthesis of choles- food intake [1]. Bile acids (BAs) facilitate fat terol both correlate with body mass index (BMI) [4– absorption. Their synthesis is regulated by nega- 6], and studies using different techniques have tive feedback [2] from BAs interacting with farne- established that they are both considerably soid X receptors (FXRs) in the liver and intestines; increased in morbid obesity [5–11], as is the the latter induces fibroblast growth factor 19 clearance of LDL from blood, despite the fact that (FGF19) [3] that suppresses the gene expression the hepatic synthesis of the LDL precursor very of CYP7A1 encoding the rate-limiting enzyme in BA low-density lipoprotein is increased [7, 12]. Impor- synthesis, cholesterol 7-alpha hydroxylase [2]. tantly, it has long been established that the faecal ª 2017 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine. 507 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Caloric restriction in obesity / S. Straniero et al. excretion of cholesterol and particularly of BAs is result of a decrease in hepatic Na+-dependent increased in morbid obesity by ~1.5-fold [6–8, 10, taurocholate co-transporting polypeptide (NTCP) 13]. Also of note, studies have consistently estab- expression [5]. lished that long-term weight reduction (13–70 kg) from caloric restriction results in normalized levels Together, the above observations strongly suggest of faecal excretion of BAs and cholesterol [6, 14]. that BAs and cholesterol are deficient in the liver in Further, and fundamental for the present study, it morbid obesity (for overview, see Fig. 1). To the has also been established that acute caloric restric- best of our knowledge, the underlying mechanism tion (300 kcal dayÀ1) very rapidly reduces faecal for the development of this phenotype amongst BA excretion by about 40% as measured in pooled morbidly obese individuals has not been stool collections already from the first 2 to 3 days addressed. However, it has been suggested that on a low-calorie diet (LCD) [13]. The faecal excre- the elevated synthesis of both cholesterol and BAs tion of cholesterol is also reduced but to a lower in obesity is due to overproduction of cholesterol in extent and more slowly [13, 14]. Recently, plasma large peripheral fat tissues, as the reduction or BAs were reported to be elevated in morbidly obese normalization of BMI results in reduced or normal- individuals [5, 15], suggested to be due to reduced ized total synthesis of cholesterol in the body active uptake of BAs from plasma to the liver as a [6, 14]. In the liver, the presumably abundant (a) (b) (c) Morbidly obese on a LCD Nonobese, BMI 22.3 Morbidly obese, BMI 41.7 for 3 days, BMI 41.1 Liver Acetyl-CoA PCSK9 Acetyl-CoA PCSK9 Acetyl-CoA PCSK9 HMG-CoAR LDLR HMG-CoAR LDLRs HMG-CoAR LDLR Cholesterol SREBP2 Cholesterol SREBP2 Cholesterol SREBP2 CYP7A1 CYP7A1 CYP7A1 Bile acids Bile acids Bile acids Stomach Bile acids & Bile acids & Bile acids & Cholesterol Cholesterol Cholesterol Portal vein Intestine Aorta Reabsorption Food mass of BAs Bile acids Cholesterol Fecal loss of bile acids and cholesterol Fig. 1 Schematic overview of the metabolic situation in nonobese control subjects (a), morbidly obese women (b) and morbidly obese women on a low-calorie diet (LCD) for 3 days (c). 508 ª 2017 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine. Journal of Internal Medicine, 2017, 281; 507–517 Caloric restriction in obesity / S. Straniero et al. cholesterol should control the level of BA synthesis protein that promotes degradation of LDL receptors via a feed-forward mechanism [6, 7, 11]. Further, it [16, 17]. has been suggested that the pronounced reduction in faecal excretion of BAs that presents following To test this hypothesis, we analysed material from caloric restriction may be due to the reduced a study in which morbidly obese individuals were synthesis of BAs that occur in parallel [13], monitored for 4 weeks after switching to an LCD although why BA synthesis is indeed reduced [18]. The primary aim of that study was to evaluate following caloric restriction has not been the time required to reduce liver volume prior to addressed. laparoscopic gastric bypass surgery. Because changing to a liquid LCD will essentially empty We reasoned that the described phenotype regard- the intestines of formed contents within 72 h [19], ing cholesterol and BA metabolism may arise from we considered the study suitable to test our a common factor amongst morbidly obese individ- hypothesis. If correct, several of the established uals that is strongly related to BMI. We hypothe- morbid obesity-related changes in BA and choles- sized that such a factor could be the higher food terol metabolism should normalize within a few intake in these individuals that will increase the days on an LCD. intestinal food mass which in turn will promote the faecal excretion of BAs and cholesterol, thereby Materials and methods creating a state of BA and cholesterol deficiency in Participants and study design the liver. The deficiency of BAs in turn will induce the expression of CYP7A1 to produce more BAs, The study design has been described elsewhere which further depletes cholesterol in the liver, [18]. Briefly, 10 morbidly obese women awaiting contributing to the transcriptional induction of laparoscopic gastric bypass surgery were recruited steroid regulatory element-binding protein-2-dri- for a prospective observational study during ven genes such as those encoding HMGCoA reduc- 4 weeks of LCD treatment. Their baseline data tase (cholesterol synthesis) and proprotein are shown in Table 1. The study was approved by convertase subtilisin/kexin type 9 (PCSK9), a the regional ethical review board in Uppsala, and Table 1 Clinical and laboratory data from 10 morbidly obese and 54 nonobese women at baseline derived from a previous cohort [4] Obese womena Nonobese womena,b (n = 10) Mean Æ SEM (n = 54) Mean Æ SD P value Age (years) 42.7 Æ 2.8 38.3 Æ 7.2 0.093 Body weight (kg) 114.4 Æ 3.8 62.1 Æ 6.3 <0.0001 BMI (kg mÀ2) 41.7 Æ 0.82 22.3 Æ 1.67 <0.0001 À Total cholesterol (mmol L 1) 4.9 Æ 0.27 4.9 Æ 0.84 0.843 LDL cholesterol (mmol LÀ1) 3.1 Æ 0.23 2.8 Æ 0.79 0.289 À HDL cholesterol (mmol L 1) 1.1 Æ 0.08 1.7 Æ 0.32 <0.0001 Total TG (mmol LÀ1) 2.0 Æ 0.43 0.9 Æ 0.35 <0.0001 À C4 (ng mL 1) 28.5 Æ 9.4 12.6 Æ 9.9 0.002 C4/c (mg molÀ1) 5.6 Æ 1.63 2.6 Æ 1.87 0.001 Total BAs (ng mLÀ1) 784 Æ 140 457 Æ 263 0.002 À Insulin (mU L 1)22Æ 9.4 4.2 Æ 2.0 <0.0001 Lathosterol (ng mLÀ1) 1615 Æ 201 1213 Æ 411 0.012 À Lathosterol/c (mg mol 1) 327 Æ 39 248 Æ 72 0.007 PCSK9 (ng mLÀ1) 349 Æ 26 268 Æ 104 0.023 À FGF19 (pg mL 1) 101 Æ 24 120 Æ 51 0.320 aAll women <50 years of age; bBMI <25 kg mÀ2.
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