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Kullberg, Joel
Publications (10 of 92) Show all publications
Boersma, G. J., Johansson, E., Pereira, M. J., Heurling, K., Skrtic, S., Lau, J., . . . Eriksson, J. (2018). Altered Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Predict Whole-Body Insulin Resistance and may Contribute to the Development of Type 2 Diabetes: A Combined PET/MR Study. Hormone and Metabolic Research, 50(8), 627-639
Open this publication in new window or tab >>Altered Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Predict Whole-Body Insulin Resistance and may Contribute to the Development of Type 2 Diabetes: A Combined PET/MR Study
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2018 (English)In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 50, no 8, p. 627-639Article in journal (Refereed) Published
Abstract [en]

We assessed glucose uptake in different tissues in type 2 diabetes (T2D), prediabetes, and control subjects to elucidate its impact in the development of whole-body insulin resistance and T2D. Thirteen T2D, 12 prediabetes, and 10 control subjects, matched for age and BMI, underwent OGTT and abdominal subcutaneous adipose tissue (SAT) biopsies. Integrated whole-body 18F-FDG PET and MRI were performed during a hyperinsulinemic euglycemic clamp to asses glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, SAT, visceral adipose tissue (VAT), and liver was significantly reduced in T2D subjects and correlated positively with M-values (r=0.884, r=0.574, r=0.707 and r=0.403, respectively). Brain MRglu was significantly higher in T2D and prediabetes subjects and had a significant inverse correlation with M-values (r=-0.616). Myocardial MRglu did not differ between groups and did not correlate with the M-values. A multivariate model including skeletal muscle, brain and VAT MRglu best predicted the M-values (adjusted r2=0.85). In addition, SAT MRglu correlated with SAT glucose uptake ex vivo (r=0.491). In different stages of the development of T2D, glucose uptake during hyperinsulinemia is elevated in the brain in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated glucose uptake in brain were independently associated with whole-body insulin resistance, and these tissue-specific alterations may contribute to T2D development.

Place, publisher, year, edition, pages
Georg Thieme Verlag KG, 2018
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-356788 (URN)10.1055/a-0643-4739 (DOI)000440872200007 ()30001566 (PubMedID)
Funder
AstraZenecaEXODIAB - Excellence of Diabetes Research in SwedenSwedish Diabetes AssociationSwedish Research CouncilErnfors Foundation
Available from: 2018-08-07 Created: 2018-08-07 Last updated: 2018-11-08Bibliographically approved
Stenlid, R., Manell, H., Halldin, M., Kullberg, J., Ahlström, H., Manukyan, L., . . . Forslund, A. (2018). High DPP-4 concentrations in adolescents are associated with low intact GLP-1. Journal of Clinical Endocrinology and Metabolism, 103(8), 2958-2966
Open this publication in new window or tab >>High DPP-4 concentrations in adolescents are associated with low intact GLP-1
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2018 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 8, p. 2958-2966Article in journal (Refereed) Published
Abstract [en]

Context: Dipeptidyl Peptidase-4 (DPP-4) metabolizes glucagon-like peptide-1 (GLP-1) and increased DPP4 levels are associated with obesity and visceral adiposity in adults.

Objective: Investigating DPP-4 levels in adolescents and association with, firstly, circulating intact GLP-1 levels and glucose tolerance, secondly, BMI, and, thirdly visceral, subcutaneous and liver fat compartments.

Design: Cross-sectional study, July 2012 to April 2015.

Setting: Pediatric obesity clinic, Uppsala University Hospital.

Patients and participants: Children and adolescents with obesity (n=59) and lean controls (n=21), age 8-18.

Main outcome measures: BMI SDS, fasting plasma concentrations of DPP-4, total and intact GLP-1, fasting and OGTT concentrations of glucose and visceral (VAT) and subcutaneous (SAT) adipose tissue volumes and liver fat fraction.

Results: Plasma DPP-4 decreased with age both in obese (41 ng/ml per year) and lean subjects (48 ng/ml per year). Plasma DPP-4 was higher in males both in the obesity and lean group. When adjusting for age and sex, plasma DPP-4 was negatively associated with intact GLP-1 at fasting, B=-12.3, 95% CI [-22.9, -1.8] and during OGTT, B=-12.1, 95% CI [-22.5, -1.7]. No associations were found between DPP-4 and plasma glucose measured at fasting or after a 2-hour OGTT. Plasma DPP-4 was 19% higher in the obese subjects. Among adipose tissue compartments the strongest association was with VAT, B=0.05, 95% CI [-0.02, 0.12].

Conclusions: In adolescents, high plasma DPP-4 concentrations are associated with low proportion of intact GLP-1, high BMI, young age and male sex. The observed associations are compatible with an increased metabolism of GLP-1 in childhood obesity.

Place, publisher, year, edition, pages
Endocrine Society, 2018
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-354234 (URN)10.1210/jc.2018-00194 (DOI)000442236900022 ()29850829 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 279153Swedish Diabetes Association, DIA 2016-146Ernfors Foundation, 160504Swedish Research Council, 2016-01040EXODIAB - Excellence of Diabetes Research in SwedenErik, Karin och Gösta Selanders Foundation
Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2018-11-05Bibliographically approved
Kjellberg, E., Roswall, J., Andersson, J., Bergman, S., Kullberg, J. & Dahlgren, J. (2018). IGF-I at Four Months Associates to Visceral and Subcutaneous Adipose Tissue at 7 Years of Age. Hormone Research in Paediatrics, 90, 93-93
Open this publication in new window or tab >>IGF-I at Four Months Associates to Visceral and Subcutaneous Adipose Tissue at 7 Years of Age
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2018 (English)In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 90, p. 93-93Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
S. Karger, 2018
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-368675 (URN)000445204100181 ()
Available from: 2018-12-06 Created: 2018-12-06 Last updated: 2018-12-06Bibliographically approved
von Below, C., Wassberg, C., Grzegorek, R., Kullberg, J., Gestblom, C., Sörensen, J., . . . Ahlström, H. (2018). MRI and 11C acetate PET/CT for prediction of regional lymph node metastasis in newly diagnosed prostate cancer. Radiology and Oncology, 52(1), 90-97
Open this publication in new window or tab >>MRI and 11C acetate PET/CT for prediction of regional lymph node metastasis in newly diagnosed prostate cancer
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2018 (English)In: Radiology and Oncology, ISSN 1318-2099, E-ISSN 1581-3207, Vol. 52, no 1, p. 90-97Article in journal (Refereed) Published
Abstract [en]

Background:

C acetate PET/CT parameters in predicting regional lymph node (LN) metastasis of newly diagnosed prostate cancer (PCa).

Patients and methods:

C acetate PET/CT (53 patients) before extended pelvic LN dissection. For each patient the visually most suspicious LN was assessed for mean apparent diffusion coefficient (ADCmean), maximal standardized uptake value (SUVmax), size and shape and the primary tumour for T stage on MRI and ADCmean and SUVmax in the index lesion. The variables were analysed in simple and multiple logistic regression analysis.

Results:

All variables, except ADCmean and SUVmax of the primary tumor, were independent predictors of LN metastasis. In multiple logistic regression analysis the best model was ADCmean in combintion with MRI T-stage where both were independent predictors of LN metastasis, this combination had an AUC of 0.81 which was higher than the AUC of 0.65 for LN ADCmean alone and the AUC of 0.69 for MRI T-stage alone.

Conclusions:

Several quantitative and qualitative imaging parameters are predictive of regional LN metastasis in PCa. The combination of ADCmean in lymph nodes and T-stage on MRI was the best model in multiple logistic regression with increased predictive value compared to lymph node ADCmean and T-stage on MRI alone.

Keywords
diffusion magnetic resonance imaging, lymph node excision, lymph nodes, positronemission tomography, prostatic neoplasm
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-346994 (URN)10.2478/raon-2018-0001 (DOI)000426260900012 ()29520210 (PubMedID)
Available from: 2018-03-23 Created: 2018-03-23 Last updated: 2018-05-16Bibliographically approved
Weis, J., Kullberg, J. & Ahlström, H. (2018). Multiple breath-hold proton spectroscopy of human liver at 3T: Relaxation times and concentrations of glycogen, choline, and lipids. Journal of Magnetic Resonance Imaging, 47, 410-417
Open this publication in new window or tab >>Multiple breath-hold proton spectroscopy of human liver at 3T: Relaxation times and concentrations of glycogen, choline, and lipids
2018 (English)In: Journal of Magnetic Resonance Imaging, ISSN 1053-1807, E-ISSN 1522-2586, Vol. 47, p. 410-417Article in journal (Refereed) Published
Abstract [en]

Purpose:

To evaluate the feasibility of an expiration multiple breath-hold H-1-MRS technique to measure glycogen (Glycg), choline-containing compounds (CCC), and lipid relaxation times T-1, T-2, and their concentrations in normal human liver.

Materials and Methods:

Thirty healthy volunteers were recruited. Experiments were performed at 3T. Multiple expiration breath-hold single-voxel point-resolved spectroscopy (PRESS) technique was used for localization. Water-suppressed spectra were used for the estimation of Glycg, CCC, lipid methylene (CH2)(n) relaxation times and concentrations. Residual water lines were removed by the Hankel Lanczos singular value decomposition filter. After phase correction and frequency alignment, spectra were averaged and processed by LCModel. Summed signals of Glycg resonances H2H4', H3, and H5 between 3.6 and 4ppm were used to estimate their apparent relaxation times and concentration. Glycg, CCC, and lipid content were estimated from relaxation corrected spectral intensity ratios to unsuppressed water line.

Results:

Relaxation times were measured for liver Glycg (T-1, 892 +/- 126 msec; T-2, 134 msec), CCC (T-1, 842 +/- 75 msec; T-2, 505 msec), lipid (CH2)(n) (T-1, 402 +/- 19 msec; T-2, 52 +/- 3 msec), and water (T-1, 990 +/- 89 msec; T-2, 30 +/- 2 msec). Mean CCC and lipid concentrations of healthy liver were 7.8 +/- 1.3 mM and 15.8 +/- 23.6 mM, respectively. Glycg content was found lower in the morning (48 +/- 21 mM) compared to the afternoon (145 +/- 50 mM).

Conclusion:

Multiple breath-hold H-1-MRS together with dedicated postprocessing is a feasible technique for the quantification of liver Glycg, CCC, and lipid relaxation times and concentrations.

Keywords
choline, glycogen, liver, magnetic resonance spectroscopy, quantification, relaxation times
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-322145 (URN)10.1002/jmri.25734 (DOI)000419991000011 ()28419608 (PubMedID)
Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2018-05-09Bibliographically approved
Gummesson, A., Strömberg, U., Schmidt, C., Kullberg, J., Angerås, O., Lindgren, S., . . . Bergström, G. (2018). Non-alcoholic fatty liver disease is a strong predictor of coronary artery calcification in metabolically healthy subjects: A cross-sectional, population-based study in middle-aged subjects.. PLoS ONE, 13(8), Article ID e0202666.
Open this publication in new window or tab >>Non-alcoholic fatty liver disease is a strong predictor of coronary artery calcification in metabolically healthy subjects: A cross-sectional, population-based study in middle-aged subjects.
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 8, article id e0202666Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: This study aims to estimate the relationship between non-alcoholic fatty liver disease (NAFLD) and measures of atherosclerotic cardiovascular disease (ASCVD), and to determine to what extent such relationships are modified by metabolic risk factors.

METHODS: The study was conducted in the population-based Swedish CArdioPulmonary bioImage Study (SCAPIS) pilot cohort (n = 1015, age 50-64 years, 51.2% women). NAFLD was defined as computed tomography liver attenuation ≤40 Hounsfield Units, excluding other causes of liver fat. Coronary artery calcification score (CACS) was assessed using the Agatston method. Carotid plaques and intima media thickness (IMT) were measured by ultrasound. Metabolic status was based on assessments of glucose homeostasis, serum lipids, blood pressure and inflammation. A propensity score model was used to balance NAFLD and non NAFLD groups with regards to potential confounders and associations between NAFLD status and ASCVD variables in relation to metabolic status were examined by logistic and generalized linear regression models.

RESULTS: NAFLD was present in 106 (10.4%) of the subjects and strongly associated with obesity-related traits. NAFLD was significantly associated with CACS after adjustment for confounders and metabolic risk factors (OR 1.77, 95% CI 1.07-2.94), but not with carotid plaques and IMT. The strongest association between NAFLD and CACS was observed in subjects with few metabolic risk factors (n = 612 [60% of all] subjects with 0-1 out of 7 predefined metabolic risk factors; OR 5.94, 95% CI 2.13-16.6).

CONCLUSIONS: NAFLD was independently associated with coronary artery calcification but not with measures of carotid atherosclerosis in this cohort. The association between NAFLD and CACS was most prominent in the metabolically healthy subjects.

National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-364359 (URN)10.1371/journal.pone.0202666 (DOI)000442500400090 ()30133541 (PubMedID)
Funder
Swedish Heart Lung FoundationSwedish Research CouncilRegion Västra Götaland
Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2018-11-27Bibliographically approved
Nylander, R., Fahlström, M., Rostrup, E., Kullberg, J., Damangir, S., Ahlström, H., . . . Larsson, E.-M. (2018). Quantitative and qualitative MRI evaluation of cerebral small vessel disease in an elderly population: a longitudinal study. Acta Radiologica, 59(5), 612-618
Open this publication in new window or tab >>Quantitative and qualitative MRI evaluation of cerebral small vessel disease in an elderly population: a longitudinal study
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2018 (English)In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 59, no 5, p. 612-618Article in journal (Refereed) Published
Abstract [en]

Background Cerebral white matter hyperintensities (WMHs), lacunes, and microbleeds are seen on magnetic resonance imaging (MRI) in small vessel disease (SVD). Purpose To assess SVD on MRI and its evolution over five years in an elderly population and to investigate whether relative cerebral blood flow (rCBF) at baseline was related to the progression of white matter (WM) lesions. Material and Methods In a population-based study, 406 participants aged 75 years underwent morphological MRI of the brain and 252 of them again at age 80 years. At age 75 years, a perfusion scan was also done. WMHs were evaluated qualitatively (visual scoring) and quantitatively (CASCADE software). Lacunes and microbleeds were counted. Results A significant progression of the WMH score and WMH volume occurred over five years ( P < 0.0001). New lacunes were seen in 10%. Participants with new lacunes at age 80 years showed a more pronounced increase in WMHs (P < 0.0001). Microbleeds were present in 14% at age 75 years. The visual WMH score was significantly associated with the presence of microbleeds ( P < 0.0001). There was no relationship between total WM rCBF and WMH volume at age 75 years, and no significant associations between regional or total rCBF at age 75 years and changes in WMH volume over five years. The total WM and GM volume decreased significantly between the ages of 75 and 80 years ( P < 0.0001). Conclusion MRI manifestations of SVD progressed over five years in an elderly population (age range = 75-80 years). rCBF was not associated with WMH volume or progression of WMH volume.

Keywords
Cerebral small vessel disease, brain, magnetic resonance imaging (MRI), perfusion, white matter
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-328693 (URN)10.1177/0284185117727567 (DOI)000429744900015 ()28814098 (PubMedID)
Available from: 2017-08-29 Created: 2017-08-29 Last updated: 2018-08-08Bibliographically approved
Johansson, E., Lubberink, M., Heurling, K., Eriksson, J. W., Skrtic, S., Ahlström, H. & Kullberg, J. (2018). Whole-Body Imaging of Tissue-specific Insulin Sensitivity and Body Composition by Using an Integrated PET/MR System: A Feasibility Study.. Radiology, 286(1), 271-278
Open this publication in new window or tab >>Whole-Body Imaging of Tissue-specific Insulin Sensitivity and Body Composition by Using an Integrated PET/MR System: A Feasibility Study.
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2018 (English)In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 286, no 1, p. 271-278Article in journal (Refereed) Published
Abstract [en]

Purpose

To develop, evaluate, and demonstrate the feasibility of a whole-body protocol for simultaneous assessment of tissue-specific insulin-mediated fluorine 18 (18F) fluorodeoxyglucose (FDG) influx rates, tissue depots, and whole-body insulin sensitivity (referred to as the M value).

Materials and Methods

An integrated positron emission tomography (PET)/magnetic resonance (MR) imaging system combined with hyperinsulinemic euglycemic clamp (HEC) was used. Dynamic whole-body PET imaging was used to determine the insulin-mediated 18F-FDG tissue influx rate (Ki) in the whole-body region by using the Patlak method. M value was determined with the HEC method at PET imaging. Tissue depots were quantified by using water-fat separated MR imaging and manual segmentations. Feasibility of the imaging protocol was demonstrated by using five healthy control participants and five patients with type 2 diabetes. Associations between M value and Ki were studied in multiple tissues by using the Pearson correlation.

Results

Positive correlations were found between M value and Ki in multiple tissues: the gluteus muscle (r = 0.875; P = .001), thigh muscle (r = 0.903; P , .001), calf muscle (r = 0.825; P = .003), and abdominal visceral adipose tissue (r = 0.820; P = .004). A negative correlation was found in the brain (r = 20.798; P = .006). The MR imaging–based method for quantification of tissue depots was feasible for determining adipose tissue volumes and fat fractions.

Conclusion

This PET/MR imaging protocol may be feasible for simultaneous assessment of tissue-specific insulin-mediated 18F-FDG influx rates, tissue depots, and M value.

National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-329272 (URN)10.1148/radiol.2017162949 (DOI)000422905200034 ()28846496 (PubMedID)
Funder
AstraZeneca
Available from: 2017-09-11 Created: 2017-09-11 Last updated: 2018-03-16Bibliographically approved
Strand, R., Malmberg, F., Johansson, L., Lind, L., Sundbom, M., Ahlström, H. & Kullberg, J. (2017). A concept for holistic whole body MRI data analysis, Imiomics. PLoS ONE, 12(2), Article ID e0169966.
Open this publication in new window or tab >>A concept for holistic whole body MRI data analysis, Imiomics
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 2, article id e0169966Article in journal (Refereed) Published
Abstract [en]

Purpose: To present and evaluate a whole-body image analysis concept, Imiomics (imaging omics) and an image registration method that enables Imiomics analyses by deforming all image data to a common coordinate system, so that the information in each voxel can be compared between persons or within a person over time and integrated with non-imaging data.

Methods: The presented image registration method utilizes relative elasticity constraints of different tissue obtained from whole-body water-fat MRI. The registration method is evaluated by inverse consistency and Dice coefficients and the Imiomics concept is evaluated by example analyses of importance for metabolic research using non-imaging parameters where we know what to expect. The example analyses include whole body imaging atlas creation, anomaly detection, and cross-sectional and longitudinal analysis.

Results: The image registration method evaluation on 128 subjects shows low inverse consistency errors and high Dice coefficients. Also, the statistical atlas with fat content intensity values shows low standard deviation values, indicating successful deformations to the common coordinate system. The example analyses show expected associations and correlations which agree with explicit measurements, and thereby illustrate the usefulness of the proposed Imiomics concept.

Conclusions: The registration method is well-suited for Imiomics analyses, which enable analyses of relationships to non-imaging data, e.g. clinical data, in new types of holistic targeted and untargeted big-data analysis.

National Category
Radiology, Nuclear Medicine and Medical Imaging
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-316830 (URN)10.1371/journal.pone.0169966 (DOI)000395934400002 ()28241015 (PubMedID)
Available from: 2017-02-27 Created: 2017-03-07 Last updated: 2017-11-29Bibliographically approved
Straniero, S., Rosqvist, F., Edholm, D., Ahlström, H., Kullberg, J., Sundbom, M., . . . Rudling, M. (2017). Acute caloric restriction counteracts hepatic bile acid and cholesterol deficiency in morbid obesity. Journal of Internal Medicine, 281(5), 507-517
Open this publication in new window or tab >>Acute caloric restriction counteracts hepatic bile acid and cholesterol deficiency in morbid obesity
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2017 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, no 5, p. 507-517Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Bile acid (BA) synthesis is regulated by BA signalling in the liver and by fibroblast growth factor 19 (FGF19), synthesized and released from the intestine. In morbid obesity, faecal excretion and hepatic synthesis of BAs and cholesterol are strongly induced and caloric restriction reduces their faecal excretion considerably. We hypothesized that the high intestinal food mass in morbidly obese subjects promotes faecal excretion of BAs and cholesterol, thereby creating a shortage of both BAs and cholesterol in the liver.

METHODS: Ten morbidly obese women (BMI 42 ± 2.6 kg m(-2) ) were monitored on days 0, 3, 7, 14 and 28 after beginning a low-calorie diet (800-1100 kcal day(-1) ). Serum was collected and liver size and fat content determined. Synthesis of BAs and cholesterol was evaluated from serum markers, and the serum levels of lipoproteins, BAs, proprotein convertase subtilisin/kexin type 9 (PCSK9), insulin, glucose and FGF19 were monitored. Fifty-four nonobese women (BMI <25 kg m(-2) ) served as controls.

RESULTS: At baseline, synthesis of both BAs and cholesterol and serum levels of BAs and PCSK9 were elevated in the obese group compared to controls. Already after 3 days on a low-calorie diet, BA and cholesterol synthesis and serum BA and PCSK9 levels normalized, whereas LDL cholesterol increased. FGF19 and triglyceride levels were unchanged, and liver volume was reduced by 10%.

CONCLUSIONS: The results suggest that hepatic BAs and cholesterol are deficient in morbid obesity. Caloric restriction rapidly counteracts these deficiencies, normalizing BA and cholesterol synthesis and circulating PCSK9 levels, indicating that overproduction of cholesterol in enlarged peripheral tissues cannot explain this phenotype. We propose that excessive food intake promotes faecal loss of BAs and cholesterol contributing to their hepatic deficiencies.

Keywords
bile acid synthesis, cholesterol synthesis, proprotein convertase subtilisin/kexin type 9
National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-316832 (URN)10.1111/joim.12599 (DOI)000399779700009 ()28261926 (PubMedID)
Funder
Swedish Research Council, 2015-02781Swedish Heart Lung Foundation, 20160491Stockholm County Council, ALF 20150447Swedish Diabetes Association
Available from: 2017-03-07 Created: 2017-03-07 Last updated: 2017-05-29Bibliographically approved
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