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Article ; Online: Intestinal Farnesoid X Receptor Modulates Duodenal Surface Area but Does Not Control Glucose Absorption in Mice.

Yang, Jiufang / van Dijk, Theo H / Koehorst, Martijn / Havinga, Rick / de Boer, Jan Freark / Kuipers, Folkert / van Zutphen, Tim

International journal of molecular sciences

2023 Volume 24, Issue 4

Abstract: Bile acids facilitate the intestinal absorption of dietary lipids and act as signalling molecules in the maintenance of metabolic homeostasis. Farnesoid X receptor (FXR) is a bile acid-responsive nuclear receptor involved in bile acid metabolism, as well ...

Abstract	Bile acids facilitate the intestinal absorption of dietary lipids and act as signalling molecules in the maintenance of metabolic homeostasis. Farnesoid X receptor (FXR) is a bile acid-responsive nuclear receptor involved in bile acid metabolism, as well as lipid and glucose homeostasis. Several studies have suggested a role of FXR in the control of genes regulating intestinal glucose handling. We applied a novel dual-label glucose kinetic approach in intestine-specific FXR
MeSH term(s)	Animals ; Mice ; Bile Acids and Salts/metabolism ; Glucose/metabolism ; Intestinal Mucosa/metabolism ; Intestines ; Mice, Inbred C57BL ; Signal Transduction
Chemical Substances	Bile Acids and Salts ; Glucose (IY9XDZ35W2) ; farnesoid X-activated receptor (0C5V0MRU6P)
Language	English
Publishing date	2023-02-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24044132
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Article ; Online: Endogenous Glucose Production in Patients With Glycogen Storage Disease Type Ia Estimated by Oral D-[6,6-2H2]-glucose.

Rossi, Alessandro / Oosterveer, Maaike H / van Dijk, Theo H / Bleeker, Aycha / Koehorst, Martijn / Weinstein, David A / Bakker, Barbara M / Derks, Terry G J

The Journal of clinical endocrinology and metabolism

2023 Volume 109, Issue 2, Page(s) 389–401

Abstract: Context: Glycogen storage disease type Ia (GSDIa) is an inborn metabolic disorder characterized by impaired endogenous glucose production (EGP). Monitoring of patients with GSDIa is prioritized because of ongoing treatment developments. Stable isotope ... ...

Abstract	Context: Glycogen storage disease type Ia (GSDIa) is an inborn metabolic disorder characterized by impaired endogenous glucose production (EGP). Monitoring of patients with GSDIa is prioritized because of ongoing treatment developments. Stable isotope tracers may enable reliable EGP monitoring. Objective: The aim of this study was to prospectively assess the rate of appearance of endogenous glucose into the bloodstream (Ra) in patients with GSDIa after a single oral D-[6,6-2H2]-glucose dose. Methods: Ten adult patients with GSDIa and 10 age-, sex-, and body mass index-matched healthy volunteers (HVs) were enrolled. For each participant, 3 oral glucose tracer tests were performed: (1) preprandial/fasted, (2) postprandial, and (3) randomly fed states. Dried blood spots were collected before D-[6,6-2H2]-glucose administration and 10, 20, 30, 40, 50, 60, 75, 90, and 120 minutes thereafter. Results: Glucose Ra in fasted HVs was consistent with previously reported data. The time-averaged glucose Ra was significantly higher in (1) preprandial/fasted patients with GSDIa than HV and (2) postprandial HV compared with fasted HV(P < .05). A progressive decrease in glucose Ra was observed in preprandial/fasted patients with GSDIa; the change in glucose Ra time-course was directly correlated with the change in capillary glucose (P < .05). Conclusion: This is the first study to quantify glucose Ra in patients with GSDIa using oral D-[6,6-2H2] glucose. The test can reliably estimate EGP under conditions in which fasting tolerance is unaffected but does not discriminate between relative contributions of EGP (eg, liver, kidney) and exogenous sources (eg, dietary cornstarch). Future application is warranted for longitudinal monitoring after novel genome based treatments in patients with GSDIa in whom nocturnal dietary management can be discontinued.
MeSH term(s)	Adult ; Humans ; Glucose/metabolism ; Glycogen Storage Disease Type I/metabolism ; Liver/metabolism ; Glucose-6-Phosphatase/metabolism ; Blood Glucose/metabolism
Chemical Substances	Glucose (IY9XDZ35W2) ; Glucose-6-Phosphatase (EC 3.1.3.9) ; Blood Glucose
Language	English
Publishing date	2023-09-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/clinem/dgad537
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Article: Milk protein oxidation in healthy subjects: A preliminary study

Reckman, Gerlof A.R / Koehorst, Martijn / Schierbeek, Henk / Vonk, Roel J

International dairy journal. 2020 Dec., v. 111

2020

Abstract: The role of protein oxidation in the regulation of whole body protein metabolism is unknown. Previously, it was observed that vigorous exercise led to increased protein oxidation. To further characterise ¹³C-milk protein oxidation in healthy subjects, ... ...

Abstract	The role of protein oxidation in the regulation of whole body protein metabolism is unknown. Previously, it was observed that vigorous exercise led to increased protein oxidation. To further characterise ¹³C-milk protein oxidation in healthy subjects, the oxidation of ingested ¹³C-protein after an overnight fast was measured using a non-invasive ¹³C-protein breath test. This approach enables the analysis of ¹³C-protein oxidation kinetics and the effect of interfering factors. It was found that the estimated maximal ¹³C-milk protein oxidation was 0.07 g min⁻¹, corresponding to a theoretical maximal oxidation capacity of ≈1.4 g kg body weight⁻¹ d⁻¹. No indications were found for preferential oxidation of non-essential amino acids. Combined ingestion of 30 g ¹³C-whey protein with 30 g glucose resulted in a 19% decrease of ¹³C-whey protein oxidation. It was concluded that exogenous ¹³C-whey protein oxidation can be affected by other co-ingested nutrients like glucose.
Keywords	body protein ; breath tests ; exercise ; glucose ; ingestion ; milk proteins ; oxidation ; protein metabolism
Language	English
Dates of publication	2020-12
Publishing place	Elsevier Ltd
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	1076400-8
ISSN	0958-6946
ISSN	0958-6946
DOI	10.1016/j.idairyj.2020.104826
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Article ; Online: Short-term obeticholic acid treatment does not impact cholangiopathy in Cyp2c70-deficient mice with a human-like bile acid composition.

Li, Rumei / Hovingh, Milaine V / Koehorst, Martijn / de Blaauw, Pim / Verkade, Henkjan J / de Boer, Jan Freark / Kuipers, Folkert

Biochimica et biophysica acta. Molecular and cell biology of lipids

2022 Volume 1867, Issue 8, Page(s) 159163

Abstract: ... ...

Abstract	Cyp2c70
MeSH term(s)	Animals ; Bile Acids and Salts ; Chenodeoxycholic Acid/analogs & derivatives ; Chenodeoxycholic Acid/pharmacology ; Female ; Fibrosis ; Humans ; Male ; Mice ; Ursodeoxycholic Acid
Chemical Substances	Bile Acids and Salts ; obeticholic acid (0462Z4S4OZ) ; Chenodeoxycholic Acid (0GEI24LG0J) ; Ursodeoxycholic Acid (724L30Y2QR)
Language	English
Publishing date	2022-04-22
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2618 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2618 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbalip.2022.159163
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Article: Short-term obeticholic acid treatment does not impact cholangiopathy in Cyp2c70-deficient mice with a human-like bile acid composition

Li, Rumei / Hovingh, Milaine V. / Koehorst, Martijn / de Blaauw, Pim / Verkade, Henkjan J. / de Boer, Jan Freark / Kuipers, Folkert

Biochimica et biophysica acta. 2022 Apr. 13,

2022

Abstract: Cyp2c70⁻/⁻ mice with a human-like bile acid (BA) composition, lacking hydrophilic muricholic acids (MCAs), have been reported to display cholangiopathy and biliary fibrosis with female preponderance that can be reversed by ursodeoxycholic acid (UDCA). ... ...

Abstract	Cyp2c70⁻/⁻ mice with a human-like bile acid (BA) composition, lacking hydrophilic muricholic acids (MCAs), have been reported to display cholangiopathy and biliary fibrosis with female preponderance that can be reversed by ursodeoxycholic acid (UDCA). Obeticholic acid (OCA), a steroidal BA-like FXR agonist, has been shown to improve liver function in patients with primary biliary cholangitis and is approved as second-line treatment for patients with an inadequate response or intolerance to UDCA. Here, we investigated the impact of OCA on BA hydrophobicity and cholangiopathy in Cyp2c70⁻/⁻ mice. Male and female wild-type (WT) and Cyp2c70⁻/⁻ mice were fed a chow diet with or without 10 mg/kg/day OCA for 4 weeks. OCA accounted for 1–5% of biliary BAs, with larger enrichments in Cyp2c70⁻/⁻ than in WT mice. In WT mice, OCA induced a more hydrophilic, MCA-rich BA pool. In Cyp2c70⁻/⁻ mice, however, BA pool became more hydrophobic with a larger proportion of chenodeoxycholic acid, attributable to a reduction of BA 12α-hydroxylation. OCA treatment reduced fecal BA excretion, indicating repression of hepatic BA synthesis in both WT and Cyp2c70⁻/⁻ mice. OCA did, however, not impact on markers of liver (dys)function in plasma nor did it ameliorate cholangiopathy and fibrosis in male or female Cyp2c70⁻/⁻ mice. OCA treatment also did not affect the expression of genes involved in fibrosis, inflammation and cellular senescence. In conclusion, 4 weeks of OCA treatment oppositely modulates the hydrophobicity of the BA pool in WT and Cyp2c70⁻/⁻ mice, but does not improve or worsen the characteristic sex-dependent liver pathology in Cyp2c70⁻/⁻ mice.
Keywords	acid treatment ; agonists ; cell senescence ; chenodeoxycholic acid ; diet ; excretion ; females ; fibrosis ; hydrophilicity ; hydrophobicity ; inflammation ; liver ; liver function ; males ; ursodeoxycholic acid
Language	English
Dates of publication	2022-0413
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ISSN	1388-1981
DOI	10.1016/j.bbalip.2022.159163
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Article ; Online: Intraintestinal fermentation of fructo- and galacto-oligosaccharides and the fate of short-chain fatty acids in humans.

van Trijp, Mara P H / Rios-Morales, Melany / Witteman, Ben / Abegaz, Fentaw / Gerding, Albert / An, Ran / Koehorst, Martijn / Evers, Bernard / van Dongen, Katja C V / Zoetendal, Erwin G / Schols, Henk / Afman, Lydia A / Reijngoud, Dirk-Jan / Bakker, Barbara M / Hooiveld, Guido J

iScience

2024 Volume 27, Issue 3, Page(s) 109208

Abstract: Consumption of fructo- (FOS) and galacto-oligosaccharides (GOS) has health benefits which have been linked in part to short-chain fatty acids (SCFA) production by the gut microbiota. However, detailed knowledge of this process in the human intestine is ... ...

Abstract	Consumption of fructo- (FOS) and galacto-oligosaccharides (GOS) has health benefits which have been linked in part to short-chain fatty acids (SCFA) production by the gut microbiota. However, detailed knowledge of this process in the human intestine is lacking. We aimed to determine the acute fermentation kinetics of a FOS:GOS mixture in healthy males using a naso-intestinal catheter for sampling directly in the ileum or colon. We studied the fate of SCFA as substrates for glucose and lipid metabolism by the host after infusion of
Language	English
Publishing date	2024-02-10
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2024.109208
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Article ; Online: Pharmacological inhibition of MEK1/2 signaling disrupts bile acid metabolism through loss of Shp and enhanced Cyp7a1 expression.

Verzijl, Cristy R C / van de Peppel, Ivo P / Eilers, Roos E / Bloks, Vincent W / Wolters, Justina C / Koehorst, Martijn / Kloosterhuis, Niels J / Havinga, Rick / Jalving, Mathilde / Struik, Dicky / Jonker, Johan W

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2023 Volume 159, Page(s) 114270

Abstract: The RAS-MAPK signaling pathway is one of the most frequently dysregulated pathways in human cancer. Small molecule inhibitors directed against this pathway have clinical activity in patients with various cancer types and can improve patient outcomes. ... ...

Abstract	The RAS-MAPK signaling pathway is one of the most frequently dysregulated pathways in human cancer. Small molecule inhibitors directed against this pathway have clinical activity in patients with various cancer types and can improve patient outcomes. However, the use of these drugs is associated with adverse effects, which can result in dose reduction or treatment interruption. A better molecular understanding of on-target, off-tumor effects may improve toxicity management. In the present study, we aimed to identify early initiating biological changes in the liver upon pharmacological inhibition of the RAS-MAPK signaling pathway. To this end, we tested the effect of MEK inhibitor PD0325901 using mice and human hepatocyte cell lines. Male C57BL/6 mice were treated with either vehicle or PD0325901 for six days, followed by transcriptome analysis of the liver and phenotypic characterization. Pharmacological MEK inhibition altered the expression of 423 genes, of which 78 were upregulated and 345 were downregulated. We identified Shp, a transcriptional repressor, and Cyp7a1, the rate-limiting enzyme in converting cholesterol to bile acids, as the top differentially expressed genes. PD0325901 treatment also affected other genes involved in bile acid regulation, which was associated with changes in the composition of plasma bile acids and composition and total levels of fecal bile acids and elevated predictive biomarkers of early liver toxicity. In conclusion, short-term pharmacological MEK inhibition results in profound changes in bile acid metabolism, which may explain some of the clinical adverse effects of pharmacological inhibition of the RAS-MAPK pathway, including gastrointestinal complications and hepatotoxicity.
MeSH term(s)	Animals ; Humans ; Male ; Mice ; Bile Acids and Salts/metabolism ; Cholesterol 7-alpha-Hydroxylase/metabolism ; Liver ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; Signal Transduction
Chemical Substances	Bile Acids and Salts ; Cholesterol 7-alpha-Hydroxylase (EC 1.14.14.23) ; CYP7A1 protein, human (EC 1.14.14.23) ; Cyp7a1 protein, mouse (EC 1.14.14.23) ; mirdametinib (86K0J5AK6M) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2) ; Receptors, Cytoplasmic and Nuclear ; nuclear receptor subfamily 0, group B, member 2
Language	English
Publishing date	2023-01-19
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2023.114270
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Article ; Online: Gut microbiota depletion aggravates bile acid-induced liver pathology in mice with a human-like bile acid composition.

Verkade, Esther / Shen, Wenqiang / Hovingh, Milaine V / Mulder, Niels L / de Bruyn, Krisztina / Koehorst, Martijn / de Vries, Hilde D / Bloks, Vincent W / Kuipers, Folkert / de Boer, Jan Freark

Clinical science (London, England : 1979)

2023 Volume 137, Issue 21, Page(s) 1637–1650

Abstract: Cyp2c70-deficient mice have a human-like bile acid (BA) composition due to their inability to convert chenodeoxycholic acid (CDCA) into rodent-specific muricholic acids (MCAs). However, the hydrophobic BA composition in these animals is associated with ... ...

Abstract	Cyp2c70-deficient mice have a human-like bile acid (BA) composition due to their inability to convert chenodeoxycholic acid (CDCA) into rodent-specific muricholic acids (MCAs). However, the hydrophobic BA composition in these animals is associated with liver pathology. Although Cyp2c70-ablation has been shown to alter gut microbiome composition, the impact of gut bacteria on liver pathology in Cyp2c70-/- mice remains to be established. Therefore, we treated young-adult male and female wild-type (WT) and Cyp2c70-/- mice with antibiotics (AB) with broad specificity to deplete the gut microbiota and assessed the consequences on BA metabolism and liver pathology. Female Cyp2c70-/- mice did not tolerate AB treatment, necessitating premature termination of the experiment. Male Cyp2c70-/- mice did tolerate AB but showed markedly augmented liver pathology after 6 weeks of treatment. Dramatic downregulation of hepatic Cyp8b1 expression (-99%) caused a reduction in the proportions of 12α-hydroxylated BAs in the circulating BA pools of AB-treated male Cyp2c70-/- mice. Interestingly, the resulting increased BA hydrophobicity strongly correlated with various indicators of liver pathology. Moreover, genetic inactivation of Cyp8b1 in livers of male Cyp2c70-/- mice increased liver pathology, while addition of ursodeoxycholic acid to the diet prevented weight loss and liver pathology in AB-treated female Cyp2c70-/- mice. In conclusion, depletion of gut microbiota in Cyp2c70-/- mice aggravates liver pathology at least in part by increasing the hydrophobicity of the circulating BA pool. These findings highlight that the potential implications of AB administration to cholestatic patients should be evaluated in a systematic manner.
MeSH term(s)	Humans ; Male ; Animals ; Female ; Mice ; Bile Acids and Salts/metabolism ; Gastrointestinal Microbiome ; Steroid 12-alpha-Hydroxylase/genetics ; Steroid 12-alpha-Hydroxylase/metabolism ; Liver/metabolism ; Cholestasis ; Anti-Bacterial Agents ; Mice, Inbred C57BL
Chemical Substances	Bile Acids and Salts ; Steroid 12-alpha-Hydroxylase (EC 1.14.18.8) ; Anti-Bacterial Agents
Language	English
Publishing date	2023-10-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	206835-7
ISSN	1470-8736 ; 0301-0538 ; 0009-0360 ; 0143-5221
ISSN (online)	1470-8736
ISSN	0301-0538 ; 0009-0360 ; 0143-5221
DOI	10.1042/CS20230812
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Article: Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in

Palmiotti, Anna / de Vries, Hilde D / Hovingh, Milaine V / Koehorst, Martijn / Mulder, Niels L / Verkade, Esther / Veentjer, Melany K / van Dijk, Theo H / Bloks, Vincent W / Havinga, Rick / Verkade, Henkjan J / de Boer, Jan Freark / Kuipers, Folkert

Biomedicines

2023 Volume 11, Issue 9

Abstract: Bile acids (BAs) and their signaling pathways have been identified as therapeutic targets for liver and metabolic diseases. We ... ...

Abstract	Bile acids (BAs) and their signaling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated
Language	English
Publishing date	2023-09-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines11092495
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Article ; Online: Hyperglycaemia, pregnancy outcomes and maternal metabolic disease risk during pregnancy and lactation in a lean gestational diabetes mouse model.

Tol, Angela J C / Hribar, Kaja / Kruit, Janine / Bongiovanni, Laura / Vieira-Lara, Marcel A / Koster, Mirjam H / Kloosterhuis, Niels J / Havinga, Rick / Koehorst, Martijn / de Bruin, Alain / Bakker, Barbara M / Oosterveer, Maaike H / van der Beek, Eline M

The Journal of physiology

2023 Volume 601, Issue 10, Page(s) 1761–1780

Abstract: Hyperglycaemia in pregnancy (HIP) is a pregnancy complication characterized by mild to moderate hyperglycaemia that negatively impacts short- and long-term health of mother and child. However, relationships between severity and timing of pregnancy ... ...

Abstract	Hyperglycaemia in pregnancy (HIP) is a pregnancy complication characterized by mild to moderate hyperglycaemia that negatively impacts short- and long-term health of mother and child. However, relationships between severity and timing of pregnancy hyperglycaemia and postpartum outcomes have not been systemically investigated. We investigated the impact of hyperglycaemia developing during pregnancy (gestational diabetes mellitus, GDM) or already present pre-mating (pre-gestational diabetes mellitus, PDM) on maternal health and pregnancy outcomes. GDM and PDM were induced in C57BL/6NTac mice by combined 60% high fat diet (HF) and low dose streptozotocin (STZ). Animals were screened for PDM prior to mating, and all underwent an oral glucose tolerance test on gestational day (GD)15. Tissues were collected at GD18 or at postnatal day (PN)15. Among HFSTZ-treated dams, 34% developed PDM and 66% developed GDM, characterized by impaired glucose-induced insulin release and inadequate suppression of endogenous glucose production. No increased adiposity or overt insulin resistance was observed. Furthermore, markers of non-alcoholic fatty liver disease (NAFLD) were significantly increased in PDM at GD18 and were positively correlated with basal glucose levels at GD18 in GDM dams. By PN15, NAFLD markers were also increased in GDM dams. Only PDM affected pregnancy outcomes such as litter size. Our findings indicate that GDM and PDM, resulting in disturbances of maternal glucose homeostasis, increase the risk of postpartum NAFLD development, related to the onset and severity of pregnancy hyperglycaemia. These findings signal a need for earlier monitoring of maternal glycaemia and more rigorous follow-up of maternal health after GDM and PDM pregnancy in humans. KEY POINTS: We studied the impact of high-fat diet/streptozotocin induced hyperglycaemia in pregnancy in mice and found that this impaired glucose tolerance and insulin release. Litter size and embryo survival were compromised by pre-gestational, but not by gestational, diabetes. Despite postpartum recovery from hyperglycaemia in a majority of dams, liver disease markers were further elevated by postnatal day 15. Maternal liver disease markers were associated with the severity of hyperglycaemia at gestational day 18. The association between hyperglycaemic exposure and non-alcoholic fatty liver disease signals a need for more rigorous monitoring and follow-up of maternal glycaemia and health in diabetic pregnancy in humans.
MeSH term(s)	Humans ; Pregnancy ; Female ; Child ; Mice ; Animals ; Diabetes, Gestational ; Hyperglycemia/complications ; Pregnancy Outcome ; Non-alcoholic Fatty Liver Disease ; Streptozocin/adverse effects ; Mice, Inbred C57BL ; Insulin ; Glucose/metabolism ; Lactation
Chemical Substances	Streptozocin (5W494URQ81) ; Insulin ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2023-04-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3115-x
ISSN	1469-7793 ; 0022-3751
ISSN (online)	1469-7793
ISSN	0022-3751
DOI	10.1113/JP284061
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