{"entity": "researcher", "timestamp": "2026-04-20T22:15:49.043Z", "family": "F\u00e4ndriks", "given": "Lars", "initials": "L", "orcid": "0000-0003-0736-3034", "affiliations": ["Institute of Clinical Sciences, Department Surgery, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/32daf05ef1f541cbbdf0b4de2fbd142e.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/32daf05ef1f541cbbdf0b4de2fbd142e"}}, "publications": [{"entity": "publication", "iuid": "46a4bd22d9ec44f4b08a35ba95cf2f70", "links": {"self": {"href": "https://publications.scilifelab.se/publication/46a4bd22d9ec44f4b08a35ba95cf2f70.json"}, "display": {"href": "https://publications.scilifelab.se/publication/46a4bd22d9ec44f4b08a35ba95cf2f70"}}, "title": "Intestinal Ketogenesis and Permeability.", "authors": [{"family": "Casselbrant", "given": "Anna", "initials": "A", "orcid": "0000-0001-7514-7435", "researcher": {"href": "https://publications.scilifelab.se/researcher/994b2b65cd154b359f5228eb0c69828b.json"}}, {"family": "Elias", "given": "Erik", "initials": "E"}, {"family": "Hallersund", "given": "Peter", "initials": "P"}, {"family": "Elebring", "given": "Erik", "initials": "E"}, {"family": "Cervin", "given": "Jakob", "initials": "J", "orcid": "0000-0002-3840-1008", "researcher": {"href": "https://publications.scilifelab.se/researcher/4d047b72260449fdb783eae2c96370eb.json"}}, {"family": "F\u00e4ndriks", "given": "Lars", "initials": "L", "orcid": "0000-0003-0736-3034", "researcher": {"href": "https://publications.scilifelab.se/researcher/32daf05ef1f541cbbdf0b4de2fbd142e.json"}}, {"family": "Wallenius", "given": "Ville", "initials": "V", "orcid": "0000-0001-8668-3196", "researcher": {"href": "https://publications.scilifelab.se/researcher/e728cf3f550046a590066de0e0cd47aa.json"}}], "type": "journal article", "published": "2024-06-14", "journal": {"title": "Int J Mol Sci", "issn": "1422-0067", "volume": "25", "issue": "12", "issn-l": null}, "abstract": "Consumption of a high-fat diet (HFD) has been suggested as a contributing factor behind increased intestinal permeability in obesity, leading to increased plasma levels of microbial endotoxins and, thereby, increased systemic inflammation. We and others have shown that HFD can induce jejunal expression of the ketogenic rate-limiting enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS). HMGCS is activated via the free fatty acid binding nuclear receptor PPAR-\u03b1, and it is a key enzyme in ketone body synthesis that was earlier believed to be expressed exclusively in the liver. The function of intestinal ketogenesis is unknown but has been described in suckling rats and mice pups, possibly in order to allow large molecules, such as immunoglobulins, to pass over the intestinal barrier. Therefore, we hypothesized that ketone bodies could regulate intestinal barrier function, e.g., via regulation of tight junction proteins. The primary aim was to compare the effects of HFD that can induce intestinal ketogenesis to an equicaloric carbohydrate diet on inflammatory responses, nutrition sensing, and intestinal permeability in human jejunal mucosa. Fifteen healthy volunteers receiving a 2-week HFD diet compared to a high-carbohydrate diet were compared. Blood samples and mixed meal tests were performed at the end of each dietary period to examine inflammation markers and postprandial endotoxemia. Jejunal biopsies were assessed for protein expression using Western blotting, immunohistochemistry, and morphometric characteristics of tight junctions by electron microscopy. Functional analyses of permeability and ketogenesis were performed in Caco-2 cells, mice, and human enteroids. Ussing chambers were used to analyze permeability. CRP and ALP values were within normal ranges and postprandial endotoxemia levels were low and did not differ between the two diets. The PPAR\u03b1 receptor was ketone body-dependently reduced after HFD. None of the tight junction proteins studied, nor the basal electrical parameters, were different between the two diets. However, the ketone body inhibitor hymeglusin increased resistance in mucosal biopsies. In addition, the tight junction protein claudin-3 was increased by ketone inhibition in human enteroids. The ketone body \u03b2-Hydroxybutyrate (\u03b2HB) did not, however, change the mucosal transition of the large-size molecular FD4-probe or LPS in Caco-2 and mouse experiments. We found that PPAR\u03b1 expression was inhibited by the ketone body \u03b2HB. As PPAR\u03b1 regulates HMGCS expression, the ketone bodies thus exert negative feedback signaling on their own production. Furthermore, ketone bodies were involved in the regulation of permeability on intestinal mucosal cells in vitro and ex vivo. We were not, however, able to reproduce these effects on intestinal permeability in vivo in humans when comparing two weeks of high-fat with high-carbohydrate diet in healthy volunteers. Further, neither the expression of inflammation markers nor the aggregate tight junction proteins were changed. Thus, it seems that not only HFD but also other factors are needed to permit increased intestinal permeability in vivo. This indicates that the healthy gut can adapt to extremes of macro-nutrients and increased levels of intestinally produced ketone bodies, at least during a shorter dietary challenge.", "doi": "10.3390/ijms25126555", "pmid": "38928261", "labels": {"Integrated Microscopy Technologies Gothenburg": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC11204016"}, {"db": "pii", "key": "ijms25126555"}], "notes": [], "created": "2024-11-15T12:02:22.117Z", "modified": "2024-11-15T12:02:22.208Z"}, {"entity": "publication", "iuid": "3d3cc74fa6f447388bea298f16fed356", "links": {"self": {"href": "https://publications.scilifelab.se/publication/3d3cc74fa6f447388bea298f16fed356.json"}, "display": {"href": "https://publications.scilifelab.se/publication/3d3cc74fa6f447388bea298f16fed356"}}, "title": "Dietary restriction and medical therapy drive PPAR\u03b1-regulated improvements in early diabetic kidney disease in male rats.", "authors": [{"family": "Martin", "given": "William P", "initials": "WP"}, {"family": "Nair", "given": "Meera", "initials": "M"}, {"family": "Chuah", "given": "Yeong H D", "initials": "YHD"}, {"family": "Malmodin", "given": "Daniel", "initials": "D"}, {"family": "Pedersen", "given": "Anders", "initials": "A"}, {"family": "Abrahamsson", "given": "Sanna", "initials": "S"}, {"family": "Hutter", "given": "Michaela", "initials": "M"}, {"family": "Abdelaal", "given": "Mahmoud", "initials": "M"}, {"family": "Elliott", "given": "Jessie A", "initials": "JA"}, {"family": "Fearon", "given": "Naomi", "initials": "N"}, {"family": "Eckhardt", "given": "Hans", "initials": "H"}, {"family": "Godson", "given": "Catherine", "initials": "C"}, {"family": "Brennan", "given": "Eoin P", "initials": "EP", "orcid": "0000-0003-4908-5474", "researcher": {"href": "https://publications.scilifelab.se/researcher/dad4628e0af94478989b5e549edbbc8a.json"}}, {"family": "F\u00e4ndriks", "given": "Lars", "initials": "L", "orcid": "0000-0003-0736-3034", "researcher": {"href": "https://publications.scilifelab.se/researcher/32daf05ef1f541cbbdf0b4de2fbd142e.json"}}, {"family": "le Roux", "given": "Carel W", "initials": "CW"}, {"family": "Docherty", "given": "Neil G", "initials": "NG"}], "type": "journal article", "published": "2022-11-11", "journal": {"title": "Clin Sci (Lond)", "issn": "1470-8736", "issn-l": null, "volume": "136", "issue": "21", "pages": "1485-1511"}, "abstract": "The attenuation of diabetic kidney disease (DKD) by metabolic surgery is enhanced by pharmacotherapy promoting renal fatty acid oxidation (FAO). Using the Zucker Diabetic Fatty and Zucker Diabetic Sprague Dawley rat models of DKD, we conducted studies to determine if these effects could be replicated with a non-invasive bariatric mimetic intervention. Metabolic control and renal injury were compared in rats undergoing a dietary restriction plus medical therapy protocol (DMT; fenofibrate, liraglutide, metformin, ramipril, and rosuvastatin) and ad libitum-fed controls. The global renal cortical transcriptome and urinary 1H-NMR metabolomic profiles were also compared. Kidney cell type-specific and medication-specific transcriptomic responses were explored through in silico deconvolution. Transcriptomic and metabolomic correlates of improvements in kidney structure were defined using a molecular morphometric approach. The DMT protocol led to \u223c20% weight loss, normalized metabolic parameters and was associated with reductions in indices of glomerular and proximal tubular injury. The transcriptomic response to DMT was dominated by changes in fenofibrate- and peroxisome proliferator-activated receptor-\u03b1 (PPAR\u03b1)-governed peroxisomal and mitochondrial FAO transcripts localizing to the proximal tubule. DMT induced urinary excretion of PPAR\u03b1-regulated metabolites involved in nicotinamide metabolism and reversed DKD-associated changes in the urinary excretion of tricarboxylic acid (TCA) cycle intermediates. FAO transcripts and urinary nicotinamide and TCA cycle metabolites were moderately to strongly correlated with improvements in glomerular and proximal tubular injury. Weight loss plus pharmacological PPAR\u03b1 agonism is a promising means of attenuating DKD.", "doi": "10.1042/CS20220205", "pmid": "36259366", "labels": {"Clinical Genomics Gothenburg": "Collaborative", "Clinical Genomics": "Collaborative", "Swedish NMR Centre": "Collaborative"}, "xrefs": [{"db": "mid", "key": "EMS156770"}, {"db": "pmc", "key": "PMC7613831"}, {"db": "pii", "key": "231957"}], "notes": [], "created": "2022-12-02T12:21:26.152Z", "modified": "2025-10-17T13:03:54.427Z"}, {"entity": "publication", "iuid": "ce0f7b27e88b45078db3fbf46d71516b", "links": {"self": {"href": "https://publications.scilifelab.se/publication/ce0f7b27e88b45078db3fbf46d71516b.json"}, "display": {"href": "https://publications.scilifelab.se/publication/ce0f7b27e88b45078db3fbf46d71516b"}}, "title": "A Fatty Diet Induces a Jejunal Ketogenesis Which Inhibits Local SGLT1-Based Glucose Transport via an Acetylation Mechanism-Results from a Randomized Cross-Over Study between Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy Volunteers.", "authors": [{"family": "Elebring", "given": "Erik", "initials": "E"}, {"family": "Wallenius", "given": "Ville", "initials": "V", "orcid": "0000-0001-8668-3196", "researcher": {"href": "https://publications.scilifelab.se/researcher/e728cf3f550046a590066de0e0cd47aa.json"}}, {"family": "Casselbrant", "given": "Anna", "initials": "A", "orcid": "0000-0001-7514-7435", "researcher": {"href": "https://publications.scilifelab.se/researcher/994b2b65cd154b359f5228eb0c69828b.json"}}, {"family": "Docherty", "given": "Neil G", "initials": "NG"}, {"family": "Roux", "given": "Carel W le", "initials": "CWL", "orcid": "0000-0001-5521-5445", "researcher": {"href": "https://publications.scilifelab.se/researcher/3def373e973945889670140361ad8ee5.json"}}, {"family": "Marschall", "given": "Hanns-Ulrich", "initials": "HU", "orcid": "0000-0001-7347-3085", "researcher": {"href": "https://publications.scilifelab.se/researcher/82b16fa78a994d12bd49ed280012893c.json"}}, {"family": "F\u00e4ndriks", "given": "Lars", "initials": "L", "orcid": "0000-0003-0736-3034", "researcher": {"href": "https://publications.scilifelab.se/researcher/32daf05ef1f541cbbdf0b4de2fbd142e.json"}}], "type": "journal article", "published": "2022-05-07", "journal": {"title": "Nutrients", "issn": "2072-6643", "volume": "14", "issue": "9", "issn-l": "2072-6643"}, "abstract": "Insights into the nature of gut adaptation after different diets enhance the understanding of how food modifications can be used to treat type 2 diabetes and obesity. The aim was to understand how diets, enriched in fat or carbohydrates, affect glucose absorption in the human healthy jejunum, and what mechanisms are involved.\n\nFifteen healthy subjects received, in randomised order and a crossover study design, two weeks of iso-caloric high-fat diet (HFD) and high-carbohydrate diet (HCD). Following each dietary period, jejunal mucosa samples were retrieved and assessed for protein expression using immunofluorescence and western blotting. Functional characterisation of epithelial glucose transport was assessed ex vivo using Ussing chambers. Regulation of SGLT1 through histone acetylation was studied in vitro in Caco-2 and human jejunal enteroid monolayer cultures.\n\nHFD, compared to HCD, decreased jejunal Ussing chamber epithelial glucose transport and the expression of apical transporters for glucose (SGLT1) and fructose (GLUT5), while expression of the basolateral glucose transporter GLUT2 was increased. HFD also increased protein expression of the ketogenesis rate-limiting enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) and decreased the acetylation of histone 3 at lysine 9 (H3K9ac). Studies in Caco-2 and human jejunal enteroid monolayer cultures indicated a ketogenesis-induced activation of sirtuins, in turn decreasing SGLT1 expression.\n\nJejunal glucose absorption is decreased by a fat-enriched diet, via a ketogenesis-induced alteration of histone acetylation responsible for the silencing of SGLT1 transcription. The work relates to a secondary outcome in ClinicalTrials.gov (NCT02088853).", "doi": "10.3390/nu14091961", "pmid": "35565929", "labels": {"Integrated Microscopy Technologies Gothenburg": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC9100393"}, {"db": "pii", "key": "nu14091961"}, {"db": "ClinicalTrials.gov", "key": "NCT02088853"}], "notes": [], "created": "2023-02-16T08:23:40.094Z", "modified": "2023-02-16T08:23:40.167Z"}, {"entity": "publication", "iuid": "25cc25920817401d9ee280754cef42da", "links": {"self": {"href": "https://publications.scilifelab.se/publication/25cc25920817401d9ee280754cef42da.json"}, "display": {"href": "https://publications.scilifelab.se/publication/25cc25920817401d9ee280754cef42da"}}, "title": "Glycemic Control and Metabolic Adaptation in Response to High-Fat versus High-Carbohydrate Diets-Data from a Randomized Cross-Over Study in Healthy Subjects.", "authors": [{"family": "Wallenius", "given": "Ville", "initials": "V", "orcid": "0000-0001-8668-3196", "researcher": {"href": "https://publications.scilifelab.se/researcher/e728cf3f550046a590066de0e0cd47aa.json"}}, {"family": "Elebring", "given": "Erik", "initials": "E"}, {"family": "Casselbrant", "given": "Anna", "initials": "A", "orcid": "0000-0001-7514-7435", "researcher": {"href": "https://publications.scilifelab.se/researcher/994b2b65cd154b359f5228eb0c69828b.json"}}, {"family": "Laurenius", "given": "Anna", "initials": "A", "orcid": "0000-0002-9150-1876", "researcher": {"href": "https://publications.scilifelab.se/researcher/26456e3b48e648749dd6353200c225bf.json"}}, {"family": "le Roux", "given": "Carel W", "initials": "CW"}, {"family": "Docherty", "given": "Neil G", "initials": "NG"}, {"family": "Bi\u00f6rserud", "given": "Christina", "initials": "C"}, {"family": "Bj\u00f6rnfot", "given": "Niclas", "initials": "N"}, {"family": "Engstr\u00f6m", "given": "My", "initials": "M", "orcid": "0000-0002-4616-468X", "researcher": {"href": "https://publications.scilifelab.se/researcher/3157542f861e40ba87731e9dd112be04.json"}}, {"family": "Marschall", "given": "Hanns-Ulrich", "initials": "HU", "orcid": "0000-0001-7347-3085", "researcher": {"href": "https://publications.scilifelab.se/researcher/82b16fa78a994d12bd49ed280012893c.json"}}, {"family": "F\u00e4ndriks", "given": "Lars", "initials": "L", "orcid": "0000-0003-0736-3034", "researcher": {"href": "https://publications.scilifelab.se/researcher/32daf05ef1f541cbbdf0b4de2fbd142e.json"}}], "type": "journal article", "published": "2021-09-23", "journal": {"title": "Nutrients", "issn": "2072-6643", "volume": "13", "issue": "10", "issn-l": "2072-6643"}, "abstract": "Granular study of metabolic responses to alterations in the ratio of dietary macro-nutrients can enhance our understanding of how dietary modifications influence patients with impaired glycemic control. In order to study the effect of diets enriched in fat or carbohydrates, fifteen healthy, normal-weight volunteers received, in a cross-over design, and in a randomized unblinded order, two weeks of an iso-caloric high-fat diet (HFD: 60E% from fat) and a high-carbohydrate diet (HCD: 60E% from carbohydrates). A mixed meal test (MMT) was performed at the end of each dietary period to examine glucose clearance kinetics and insulin and incretin hormone levels, as well as plasma metabolomic profiles. The MMT induced almost identical glycemia and insulinemia following the HFD or HCD. GLP-1 levels were higher after the HFD vs. HCD, whereas GIP did not differ. The HFD, compared to the HCD, increased the levels of several metabolomic markers of risk for the development of insulin resistance, e.g., branched-chain amino acid (valine and leucine), creatine and \u03b1-hydroxybutyric acid levels. In normal-weight, healthy volunteers, two weeks of the HFD vs. HCD showed similar profiles of meal-induced glycemia and insulinemia. Despite this, the HFD showed a metabolomic pattern implying a risk for a metabolic shift towards impaired insulin sensitivity in the long run.", "doi": "10.3390/nu13103322", "pmid": "34684324", "labels": {"Swedish NMR Centre": "Service"}, "xrefs": [{"db": "pii", "key": "nu13103322"}, {"db": "pmc", "key": "PMC8538379"}], "notes": [], "created": "2021-12-08T15:46:09.857Z", "modified": "2025-10-17T13:03:55.570Z"}]}