Postprandial metabolism of apolipoproteins B48, B100, C-III, and E in humans with APOC3 loss-of-function mutations

BACKGROUND. Apolipoprotein C-III (apoC-III) is a regulator of triglyceride (TG) metabolism, and due to its association with risk of cardiovascular disease, is an emergent target for pharmacological intervention. The impact of substantially lowering apoC-III on lipoprotein metabolism is not clear.METHODS. We investigated the kinetics of apolipoproteins B48 and B100 (apoB48 and apoB100) in chylomicrons, VLDL1, VLDL2, IDL, and LDL in patients heterozygous for a loss-of-function (LOF) mutation in the APOC3 gene. Studies were conducted in the postprandial state to provide a more comprehensive view of the influence of this protein on TG transport.RESULTS. Compared with non-LOF variant participants, a genetically determined decrease in apoC-III resulted in marked acceleration of lipolysis of TG-rich lipoproteins (TRLs), increased removal of VLDL remnants from the bloodstream, and substantial decrease in circulating levels of VLDL1, VLDL2, and IDL particles. Production rates for apoB48-containing chylomicrons and apoB100-containing VLDL1 and VLDL2 were not different between LOF carriers and noncarriers. Likewise, the rate of production of LDL was not affected by the lower apoC-III level, nor were the concentration and clearance rate of LDL-apoB100.CONCLUSION. These findings indicate that apoC-III lowering will have a marked effect on TRL and remnant metabolism, with possibly significant consequences for cardiovascular disease prevention. TRIAL REGISTRATION. ClinicalTrials.gov NCT04209816 and NCT01445730.Peer reviewe

An Integrated Understanding of the Rapid Metabolic Benefits of a Carbohydrate-Restricted Diet on Hepatic Steatosis in Humans

A carbohydrate-restricted diet is a widely recommended intervention for non-alcoholic fatty liver disease (NAFLD), but a systematic perspective on the multiple benefits of this diet is lacking. Here, we performed a short-term intervention with an isocaloric low-carbohydrate diet with increased protein content in obese subjects with NAFLD and characterized the resulting alterations in metabolism and the gut microbiota using a multi-omics approach. We observed rapid and dramatic reductions of liver fat and other cardiometabolic risk factors paralleled by (1) marked decreases in hepatic de novo lipogenesis; (2) large increases in serum beta-hydroxybutyrate concentrations, reflecting increased mitochondrial beta-oxidation; and (3) rapid increases in folate-producing Streptococcus and serum folate concentrations. Liver transcriptomic analysis on biopsy samples from a second cohort revealed downregulation of the fatty acid synthesis pathway and upregulation of folate-mediated one-carbon metabolism and fatty acid oxidation pathways. Our results highlight the potential of exploring diet-microbiota interactions for treating NAFLD.Peer reviewe

Duodenal Anaerobutyricum soehngenii infusion stimulates GLP-1 production, ameliorates glycaemic control and beneficially shapes the duodenal transcriptome in metabolic syndrome subjects : a randomised double-blind placebo-controlled cross-over study

Objective Although gut dysbiosis is increasingly recognised as a pathophysiological component of metabolic syndrome (MetS), the role and mode of action of specific gut microbes in metabolic health remain elusive. Previously, we identified the commensal butyrogenic Anaerobutyricum soehngenii to be associated with improved insulin sensitivity in subjects with MetS. In this proof-of-concept study, we investigated the potential therapeutic effects of A. soehngenii L2-7 on systemic metabolic responses and duodenal transcriptome profiles in individuals with MetS. Design In this randomised double-blind placebo-controlled cross-over study, 12 male subjects with MetS received duodenal infusions of A. soehngenii/ placebo and underwent duodenal biopsies, mixed meal tests (6 hours postinfusion) and 24-hour continuous glucose monitoring. Results A. soehngenii treatment provoked a markedly increased postprandial excursion of the insulinotropic hormone glucagon-like peptide 1 (GLP-1) and an elevation of plasma secondary bile acids, which were positively associated with GLP-1 levels. Moreover, A. soehngenii treatment robustly shaped the duodenal expression of 73 genes, with the highest fold induction in the expression of regenerating islet-protein 1B (REG1B)-encoding gene. Strikingly, duodenal REG1B expression positively correlated with GLP-1 levels and negatively correlated with peripheral glucose variability, which was significantly diminished in the 24 hours following A. soehngenii intake. Mechanistically, Reg1B expression is induced upon sensing butyrate or bacterial peptidoglycan. Importantly, A. soehngenii duodenal administration was safe and well tolerated. Conclusions A single dose of A. soehngenii improves peripheral glycaemic control within 24 hours; it specifically stimulates intestinal GLP-1 production and REG1B expression. Further studies are needed to delineate the specific pathways involved in REG1B induction and function in insulin sensitivity.Peer reviewe

Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism

Properties of Swedish Posttraumatic Stress Measures after a Disaster

This study evaluated the properties of Swedish versions of self-report measures of posttraumatic stress disorder (PTSD), with emphasis on the Impact of Event Scale–Revised (IES-R). Survey data from adult survivors 1, 3, and 6 years after the 2004 Indian Ocean tsunami (n = 1506) included the IES-R (from which the IES-6 was derived) and the 12-item General Health Questionnaire (GHQ-12). The PTSD Checklist (PCL) was included in one survey. A structured clinical interview was performed after 6 years (n = 142). Factor analyses of the IES-R and PCL indicated that a dysphoric-arousal model provided good fit invariant across assessments. Both measures were accurate in excluding PTSD while all measures provided poorer positive predictive values. The IES-R, but not the IES-6 and GHQ-12, evidenced stability across assessments. In conclusion, the Swedish IES-R and PCL are sound measures of chronic PTSD, and the findings illustrate important temporal aspects of PTSD assessment

Prevalence and Duration of PTSD in Survivors Six Years After a Natural Disaster

The present study aimed to examine the prevalence of posttraumatic stress disorder (PTSD) in survivors with low levels of risk factors for PTSD. The sample included 142 adults (58% women, 54% university education, 93% employed/students/retired) on vacation in Southeast Asia during the 2004 Indian Ocean disaster. Semi-structured clinical interviews (SCID-I) were performed after 6 years including PTSD, depression, specific phobia, and alcohol abuse. The 6-year prevalence of PTSD was 11.3% and the current prevalence was 4.2%, with onset mainly within 1 month and remission within 3 years post-disaster. Suicidal ideation and comorbidity were common in PTSD cases. Lifetime prevalence of depression was 19%, specific phobia 7%, and alcohol abuse 4%. The findings suggest elevated levels of PTSD but not other disorders as compared with general population samples, but still lower levels than other disaster samples. Despite benign circumstances, however, the course and burden of PTSD were comparable to similar studies

Prevalence and Duration of PTSD in Survivors Six Years After a Natural Disaster

The present study aimed to examine the prevalence of posttraumatic stress disorder (PTSD) in survivors with low levels of risk factors for PTSD. The sample included 142 adults (58% women, 54% university education, 93% employed/students/retired) on vacation in Southeast Asia during the 2004 Indian Ocean disaster. Semi-structured clinical interviews (SCID-I) were performed after 6 years including PTSD, depression, specific phobia, and alcohol abuse. The 6-year prevalence of PTSD was 11.3% and the current prevalence was 4.2%, with onset mainly within 1 month and remission within 3 years post-disaster. Suicidal ideation and comorbidity were common in PTSD cases. Lifetime prevalence of depression was 19%, specific phobia 7%, and alcohol abuse 4%. The findings suggest elevated levels of PTSD but not other disorders as compared with general population samples, but still lower levels than other disaster samples. Despite benign circumstances, however, the course and burden of PTSD were comparable to similar studies