Background characteristics and neuropathology findings of medico-legal autopsy cases with and without ß-amyloid precursor protein positive diffuse traumatic axonal injury.

The postmortem diagnosis of diffuse traumatic axonal injury (dTAI) relies on ß-amyloid precursor protein (ß-APP) immunohistochemistry. Most reports of factors associating with dTAI are decades old. We compared background characteristics and neuropathology findings of today's Finnish medico-legal autopsy cases with and without ß-APP-positive dTAI (dTAI+ and dTAI-, respectively). The cases had suffered a head injury prior to death and underwent a full neuropathological examination including ß-APP stain. Background and circumstantial data as well as neuropathology findings were collected from police documents, medical records, and autopsy and neuropathology reports. Prevalence ratios were calculated for each factor to facilitate comparisons between the dTAI+ and dTAI- groups. The dataset comprised 57 cases (66.7% males), with 17 classified as dTAI+ and 40 as dTAI-. Based on prevalence ratios, the factors that had at least two-fold prevalence among dTAI+ cases compared to dTAI- cases were: an unknown injury mechanism; concurrent epidural or subdural haemorrhage; and an accidental manner of death. In contrast, the factors that had at least two-fold prevalence among dTAI- cases compared to dTAI+ cases were: a short postinjury survival (<30 min); concurrent intracerebral/ventricular haemorrhage or contusion; vermal atrophy; and a natural or homicidal manner of death. This study revealed differences in circumstantial features and neuropathology findings between dTAI+ and dTAI- cases in today's medico-legal autopsy material. Data on typical case profiles may help estimate the prior probability of dTAI not only in medico-legal autopsies but also among living patients with head injuries.

Contribution of intestinal triglyceride-rich lipoproteins to residual atherosclerotic cardiovascular disease risk in individuals with type 2 diabetes on statin therapy.

AIMS/HYPOTHESIS: This study explored the hypothesis that significant abnormalities in the metabolism of intestinally derived lipoproteins are present in individuals with type 2 diabetes on statin therapy. These abnormalities may contribute to residual CVD risk. METHODS: To investigate the kinetics of ApoB-48- and ApoB-100-containing lipoproteins, we performed a secondary analysis of 11 overweight/obese individuals with type 2 diabetes who were treated with lifestyle counselling and on a stable dose of metformin who were from an earlier clinical study, and compared these with 11 control participants frequency-matched for age, BMI and sex. Participants in both groups were on a similar statin regimen during the study. Stable isotope tracers were used to determine the kinetics of the following in response to a standard fat-rich meal: (1) apolipoprotein (Apo)B-48 in chylomicrons and VLDL; (2) ApoB-100 in VLDL, intermediate-density lipoprotein (IDL) and LDL; and (3) triglyceride (TG) in VLDL. RESULTS: The fasting lipid profile did not differ significantly between the two groups. Compared with control participants, in individuals with type 2 diabetes, chylomicron TG and ApoB-48 levels exhibited an approximately twofold higher response to the fat-rich meal, and a twofold higher increment was observed in ApoB-48 particles in the VLDL1 and VLDL2 density ranges (all p < 0.05). Again comparing control participants with individuals with type 2 diabetes, in the latter, total ApoB-48 production was 25% higher (556 ± 57 vs 446 ± 57 mg/day; p < 0.001), conversion (fractional transfer rate) of chylomicrons to VLDL was around 40% lower (35 ± 25 vs 82 ± 58 pools/day; p=0.034) and direct clearance of chylomicrons was 5.6-fold higher (5.6 ± 2.2 vs 1.0 ± 1.8 pools/day; p < 0.001). During the postprandial period, ApoB-48 particles accounted for a higher proportion of total VLDL in individuals with type 2 diabetes (44%) compared with control participants (25%), and these ApoB-48 VLDL particles exhibited a fivefold longer residence time in the circulation (p < 0.01). No between-group differences were seen in the kinetics of ApoB-100 and TG in VLDL, or in LDL ApoB-100 production, pool size and clearance rate. As compared with control participants, the IDL ApoB-100 pool in individuals with type 2 diabetes was higher due to increased conversion from VLDL2. CONCLUSIONS/INTERPRETATION: Abnormalities in the metabolism of intestinally derived ApoB-48-containing lipoproteins in individuals with type 2 diabetes on statins may help to explain the residual risk of CVD and may be suitable targets for interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02948777.

Deep Learning Neural Network-Guided Detection of Asbestos Bodies in Bronchoalveolar Lavage Samples.

INTRODUCTION: Asbestos is a global occupational health hazard, and exposure to it by inhalation predisposes to interstitial as well as malignant pulmonary morbidity. Over time, asbestos fibers embedded in lung tissue can become coated with iron-rich proteins and mucopolysaccharides, after which they are called asbestos bodies (ABs) and can be detected in light microscopy (LM). Bronchoalveolar lavage, a cytological sample from the lower airways, is one of the methods for diagnosing lung asbestosis and related morbidity. Search for ABs in these samples is generally laborious and time-consuming. We describe a novel diagnostic method, which implements deep learning neural network technology for the detection of ABs in bronchoalveolar lavage samples (BALs). METHODS: BALs with suspicion of asbestos exposure were scanned as whole slide images (WSIs) and uploaded to a cloud-based virtual microscopy platform with a neural network training interface. The images were used for training and testing a neural network model capable of recognizing ABs. To prioritize the model's sensitivity, we allowed it to also make false-positive suggestions. To test the model, we compared its performance to standard LM diagnostic data as well as the ground truth (GT) number of ABs, which we established by a thorough manual search of the WSIs. RESULTS: We were able to reach overall sensitivity of 93.4% (95% CI: 90.3-95.7%) in the detection of ABs in comparison to their GT number. Compared to standard LM diagnostic data, our model showed equal to or higher sensitivity in most cases. CONCLUSION: Our results indicate that deep learning neural network technology offers promising diagnostic tools for routine assessment of BALs. However, at this stage, a human expert is required to confirm the findings.

Forensic neuropathology in the past decade: a scoping literature review.

While there has been notable research activity in the field of clinical neuropathology over the recent years, forensic approaches have been less frequent. This scoping literature review explored original research on forensic neuropathology over the past decade (January 1, 2010, until February 12, 2022) using the MEDLINE database. The aims were to (1) analyze the volume of research on the topic, (2) describe meta-level attributes and sample characteristics, and (3) summarize key research themes and methods. Of 5053 initial hits, 2864 fell within the target timeframe, and 122 were included in the review. Only 3-17 articles were published per year globally. Most articles originated from the Europe (39.3%) and Asia (36.1%) and were published in forensic journals (57.4%). A median sample included 57 subjects aged between 16 and 80 years. The most common research theme was traumatic intracranial injury (24.6%), followed by anatomy (12.3%) and substance abuse (11.5%). Key methods included immunotechniques (31.1%) and macroscopic observation (21.3%). Although a number of novel findings were reported, most were of preliminary nature and will require further validation. In order to reach breakthroughs and validate novel tools for routine use, more research input is urged from researchers across the world. It would be necessary to ensure appropriate sample sizes and make use of control groups.

Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study.

Nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide riboside (NR) has emerged as a promising compound to improve obesity-associated mitochondrial dysfunction and metabolic syndrome in mice. However, most short-term clinical trials conducted so far have not reported positive outcomes. Therefore, we aimed to determine whether long-term NR supplementation boosts mitochondrial biogenesis and metabolic health in humans. Twenty body mass index (BMI)-discordant monozygotic twin pairs were supplemented with an escalating dose of NR (250 to 1000 mg/day) for 5 months. NR improved systemic NAD+ metabolism, muscle mitochondrial number, myoblast differentiation, and gut microbiota composition in both cotwins. NR also showed a capacity to modulate epigenetic control of gene expression in muscle and adipose tissue in both cotwins. However, NR did not ameliorate adiposity or metabolic health. Overall, our results suggest that NR acts as a potent modifier of NAD+ metabolism, muscle mitochondrial biogenesis and stem cell function, gut microbiota, and DNA methylation in humans irrespective of BMI.

Identification of Gut Microbial Lysine and Histidine Degradation and CYP-Dependent Metabolites as Biomarkers of Fatty Liver Disease.

Numerous studies have described specific metabolites as biomarkers of severe liver diseases, but very few have measured gut microbiota (GM)-produced metabolites in fatty liver disease. We aimed at finding GM signatures and metabolite markers in plasma and feces related to high liver fat content. Based on imaging, we divided study participants into low (<5%, LF, n = 25) and high (>5%, HF, n = 39) liver fat groups. Fecal (LF n = 14, HF n = 25) and plasma (LF n = 11, HF n = 7) metabolomes of subsets of participants were studied using liquid chromatography/high resolution mass spectrometry. The GM were analyzed using 16S rRNA gene sequencing. Additionally, blood clinical variables and diet were studied. Dyslipidemia, higher liver enzymes and insulin resistance characterized the HF group. No major differences in diet were found between the groups. In the GM, the HF group had lower abundance of Bacteroides and Prevotellaceae NK3B31 group than the LF group after adjusting for metformin use or obesity. In feces, the HF group had higher levels of lysine and histidine degradation products, while 6-hydroxybetatestosterone (metabolized by CYP3A4) was low. Higher plasma levels of caffeine and its metabolites in the HF group indicate that the activity of hepatic CYP1A2 was lower than in the LF group. Our results suggest, that low fecal Prevotellaceae NK3B31 and Bacteroides abundance, and increased lysine and histidine degradation may serve as GM biomarkers of high liver fat. Altered plasma caffeine metabolites and lowered testosterone metabolism may specify decreased CYP activities, and their potential utility, as biomarkers of fatty liver disease. IMPORTANCE Because the high prevalence of nonalcoholic fatty liver disease sets diagnostic challenges to health care, identification of new biomarkers of the disease that in the future could have potential utility as diagnostic biomarkers of high liver fat content is important. Our results show that increased amino acid degradation products in the feces may be such biomarkers. In the blood, molecules that indicate defective hepatic metabolic enzyme activities were identified in individuals with high liver fat content.

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

BackgroundApolipoprotein 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.MethodsWe 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.ResultsCompared 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.ConclusionThese 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 registrationClinicalTrials.gov NCT04209816 and NCT01445730.FundingSwedish Heart-Lung Foundation, Swedish Research Council, ALF grant from the Sahlgrenska University Hospital, Novo Nordisk Foundation, Sigrid Juselius Foundation, Helsinki University Hospital Government Research funds, Finnish Heart Foundation, and Finnish Diabetes Research Foundation.

Abdominal adipose tissue and liver fat imaging in very low birth weight adults born preterm: birth cohort with sibling-controls.

Preterm birth at very low birth weight (VLBW, < 1500 g) is associated with an accumulation of cardiovascular and metabolic risk factors from childhood at least to middle age. Small-scale studies suggest that this could partly be explained by increased visceral or ectopic fat. We performed magnetic resonance imaging on 78 adults born preterm at VLBW in Finland between 1978 and 1990 and 72 term same-sex siblings as controls, with a mean age of 29 years. We collected T1-weighted images from the abdomen, and magnetic resonance spectra from the liver, subcutaneous abdominal adipose tissue, and tibia. The adipose tissue volumes of VLBW adults did not differ from their term siblings when adjusting for age, sex, and maternal and perinatal factors. The mean differences were as follows: subcutaneous - 0.48% (95% CI - 14.8%, 16.3%), visceral 7.96% (95% CI - 10.4%, 30.1%), and total abdominal fat quantity 1.05% (95% CI - 13.7%, 18.4%). Hepatic triglyceride content was also similar. VLBW individuals displayed less unsaturation in subcutaneous adipose tissue (- 4.74%, 95% CI - 9.2%, - 0.1%) but not in tibial bone marrow (1.68%, 95% CI - 1.86%, 5.35%). VLBW adults displayed similar adipose tissue volumes and hepatic triglyceride content as their term siblings. Previously reported differences could thus partly be due to genetic or environmental characteristics shared between siblings. The VLBW group displayed less unsaturation in subcutaneous abdominal adipose tissue, suggesting differences in its metabolic activity and energy storage.

Role of endogenous incretins in the regulation of postprandial lipoprotein metabolism.

Objective: Incretins are known to influence lipid metabolism in the intestine when administered as pharmacologic agents. The aggregate influence of endogenous incretins on chylomicron production and clearance is less clear, particularly in light of opposing effects of co-secreted hormones. Here, we tested the hypothesis that physiological levels of incretins may impact on production or clearances rates of chylomicrons and VLDL. Design and methods: A group of 22 overweight/obese men was studied to determine associations between plasma levels of glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) after a fat-rich meal and the production and clearance rates of apoB48- and apoB100-containing triglyceride-rich lipoproteins. Subjects were stratified by above- and below-median incretin response (area under the curve). Results: Stratification yielded subgroups that differed about two-fold in incretin response. There were neither differences in apoB48 production rates in chylomicrons or VLDL fractions nor in apoB100 or triglyceride kinetics in VLDL between men with above- vs below-median incretin responses. The men with above-median GLP-1 and GLP-2 responses exhibited higher postprandial plasma and chylomicron triglyceride levels, but this could not be related to altered kinetic parameters. No differences were found between incretin response subgroups and particle clearance rates. Conclusion: We found no evidence for a regulatory effect of endogenous incretins on contemporaneous chylomicron or VLDL metabolism following a standardised fat-rich meal. The actions of incretins at pharmacological doses may not be reflected at physiological levels of these hormones.

Matrisome alterations in obesity - Adipose tissue transcriptome study on monozygotic weight-discordant twins.

Adipose tissue is a central regulator of metabolic health and its failure in obesity is a major cause of weight associated comorbidities, such as type 2 diabetes. Many extracellular matrix proteins, represented by matrisome, play a critical role in balancing adipose tissue health and dysfunction. Extracellular matrix components, produced by different cell types of adipose tissue, can modulate adipocyte function, tissue remodeling during expansion, angiogenesis, and inflammation and also form fibrotic lesions in the tissue. In this study, we investigated changes in matrisome of whole adipose tissue and adipocytes in human obesity. We investigated further the networks and biological pathways of the genes related to the changes and their association to development of metabolic dysfunction linked to type 2 diabetes. We used transcriptome data and clinical metabolic parameters from a rare weight-discordant MZ twin cohort. The Heavy-Lean differential matrisome gene expression (Δmatrisome) and differential metabolic parameters reflect changes in adipose tissue upon weight gain and changes in whole body glucose, insulin metabolism, as well as lipid status. We report that obesity Δmatrisome shows high specificity with 130 and 71 of the 1068 matrisome genes showing altered expression in the adipose tissue and adipocytes of heavier co-twin, respectively. The Δmatrisome differs considerably between adipose tissue vs adipocytes which reflects inflammation of hypertrophic adipocytes and the remodeling activity of the rest of the tissue resident cells. The obesity Δmatrisome is discussed extensively in the light of existing evidence and novel significant associations to obesity are reported to matrisome genes; cathepsin A, cathepsin O, FAM20B and N-glycanase1.

Brain Volumes and Abnormalities in Adults Born Preterm at Very Low Birth Weight.

OBJECTIVES: To assess radiographic brain abnormalities and investigate volumetric differences in adults born preterm at very low birth weight (<1500 g), using siblings as controls. STUDY DESIGN: We recruited 79 adult same-sex sibling pairs with one born preterm at very low birth weight and the sibling at term. We acquired 3-T brain magnetic resonance imaging from 78 preterm participants and 72 siblings. A neuroradiologist, masked to participants' prematurity status, reviewed the images for parenchymal and structural abnormalities, and FreeSurfer software 6.0 was used to conduct volumetric analyses. Data were analyzed by linear mixed models. RESULTS: We found more structural abnormalities in very low birth weight participants than in siblings (37% vs 13%). The most common finding was periventricular leukomalacia, present in 15% of very low birth weight participants and in 3% of siblings. The very low birth weight group had smaller absolute brain volumes (-0.4 SD) and, after adjusting for estimated intracranial volume, less gray matter (-0.2 SD), larger ventricles (1.5 SD), smaller thalami (-0.6 SD), caudate nuclei (-0.4 SD), right hippocampus (-0.4 SD), and left pallidum (-0.3 SD). We saw no volume differences in total white matter (-0.04 SD; 95% CI, -0.13 to 0.09). CONCLUSIONS: Preterm very low birth weight adults had a higher prevalence of brain abnormalities than their term-born siblings. They also had smaller absolute brain volumes, less gray but not white matter, and smaller volumes in several gray matter structures.

Longitudinal evolution of catheter-related bloodstream infections, kidney function and liver status in a nationwide adult intestinal failure cohort.

OBJECTIVES: The development of intestinal failure-related complications in Finnish adults is unknown. This study aimed to investigate the incidence of catheter-related bloodstream infections (CRBSI), and the longitudinal changes in biochemical liver and kidney tests in a nationwide cohort. MATERIALS AND METHODS: The search for Finnish adults with intestinal failure (IF) utilized a survey to Finnish health-care providers (n = 111) with the potential to provide long-term parenteral support (PS) for adult IF. Our nationwide, cross-sectional cohort included all IF patients aged ≥ 18 years who had received PS for ≥ 120 d in 2017. Data regarding CRBSI and biochemical liver and kidney tests were collected from patient records at the start of PS up to the latest available measurement in 2017. RESULTS: In the nationwide cohort of 52 patients, the CRBSI incidence was 1.35/1000 catheter days. Seventy-three percent of CRBSI in a long-term catheter led to catheter replacement. During a median PS duration of 27.5 (interquartile range [IQR] 11.3-57.3) months, a statistically significant median change occurred in estimated glomerular filtration rate (eGFR; -8.5 ml/min/1.73 m2, IQR -30-7, p = .005) and alkaline phosphatase (ALP; 26 U/l, IQR -11-95, p = .019). In a multiple regression model for eGFR at data collection, baseline eGFR and age were strong explanatory variables. CONCLUSIONS: Incidence of CRBSI, but not treatment strategies, in this nationwide adult IF population correspond well to those reported from specialized centers. Decreased kidney function and abnormal liver test results are frequent findings, and even more so over time, emphasizing the importance of regular monitoring.

Effects of PNPLA3 I148M on hepatic lipid and very-low-density lipoprotein metabolism in humans.

BACKGROUND: The phospholipase domain-containing 3 gene (PNPLA3)-148M variant is associated with liver steatosis but its influence on the metabolism of triglyceride-rich lipoproteins remains unclear. Here, we investigated the kinetics of large, triglyceride-rich very-low-density lipoprotein (VLDL), (VLDL1 ), and smaller VLDL2 in homozygotes for the PNPLA3-148M variant. METHODS AND RESULTS: The kinetics of apolipoprotein (apo) B100 (apoB100) and triglyceride in VLDL subfractions were analysed in nine subjects homozygous for PNPLA3-148M and nine subjects homozygous for PNPLA3-148I (controls). Liver fat was >3-fold higher in the 148M subjects. Production rates for apoB100 and triglyceride in VLDL1 did not differ significantly between the two groups. Likewise, production rates for VLDL2 -apoB100 and -triglyceride, and fractional clearance rates for both apoB100 and triglyceride in VLDL1 and VLDL2 , were not significantly different. CONCLUSIONS: Despite the higher liver fat content in PNPLA3 148M homozygotes, there was no increase in VLDL production. Equally, VLDL production was maintained at normal levels despite the putative impairment in cytosolic lipid hydrolysis in these subjects.

Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease.

BACKGROUND & AIMS: There is substantial inter-individual variability in the risk of non-alcoholic fatty liver disease (NAFLD). Part of which is explained by insulin resistance (IR) ('MetComp') and part by common modifiers of genetic risk ('GenComp'). We examined how IR on the one hand and genetic risk on the other contribute to the pathogenesis of NAFLD. METHODS: We studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D5-glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D2O (n = 61). RESULTS: We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the 'MetComp'. In contrast, the 'GenComp' was not accompanied by any substrate excess but was characterized by an increased hepatic mitochondrial redox state, as determined by serum ß-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum ß-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD. CONCLUSIONS: These data show that the mechanisms underlying 'Metabolic' and 'Genetic' components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD. LAY SUMMARY: The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates.

Liver Fat, Adipose Tissue, and Body Composition Changes After Switching from a Protease Inhibitor or Efavirenz to Raltegravir.

Integrase inhibitors appear to increase body weight, but paradoxically some data indicate that raltegravir (RAL) may decrease liver fat. Our objective was to study the effects of switching from a protease inhibitor (PI) or efavirenz (EFV) to RAL on liver fat, body composition, and metabolic parameters among people living with HIV (PLWH) with high risk for nonalcoholic fatty liver disease (NAFLD). We randomized overweight PLWH with signs of metabolic syndrome to switch a PI or EFV to RAL (n = 19) or to continue unchanged antiretroviral therapy (control, n = 24) for 24 weeks. Liver fat was measured by magnetic resonance spectroscopy (MRS), body composition by magnetic resonance imaging, and bioimpedance analysis; subcutaneous fat biopsies were obtained. Median (interquartile range) liver fat content was normal in RAL 2.3% (1.1-6.0) and control 3.1% (1.6-7.3) group at baseline. Liver fat and visceral adipose tissue remained unchanged during the study. Body weight [from 85.9 kg (76.1-97.7) to 89.3 (78.7-98.7), p = 0.019], body fat mass [from 20.3 kg (14.6-29.7) to 22.7 (17.0-29.7), p = 0.015], and subcutaneous adipose tissue (SAT) volume [from 3979 mL (2068-6468) to 4043 (2206-6433), p = 0.048] increased, yet, adipocyte size [from 564 pL (437-733) to 478 (423-587), p = 0.019] decreased in RAL but remained unchanged in control group. Circulating lipids and inflammatory markers improved in RAL compared to control group. The median liver fat measured by MRS was unexpectedly within normal range in this relatively small study population with presumably high risk for NAFLD contradicting high prevalence of NAFLD reported with other methods. Despite weight gain, increase in SAT together with decreased adipocyte size and reduced inflammation may reflect improved adipose tissue function. Clinical Trial Registration number: NCT03374358.

Molecular pathways behind acquired obesity: Adipose tissue and skeletal muscle multiomics in monozygotic twin pairs discordant for BMI.

Tissue-specific mechanisms prompting obesity-related development complications in humans remain unclear. We apply multiomics analyses of subcutaneous adipose tissue and skeletal muscle to examine the effects of acquired obesity among 49 BMI-discordant monozygotic twin pairs. Overall, adipose tissue appears to be more affected by excess body weight than skeletal muscle. In heavier co-twins, we observe a transcriptional pattern of downregulated mitochondrial pathways in both tissues and upregulated inflammatory pathways in adipose tissue. In adipose tissue, heavier co-twins exhibit lower creatine levels; in skeletal muscle, glycolysis- and redox stress-related protein and metabolite levels remain higher. Furthermore, metabolomics analyses in both tissues reveal that several proinflammatory lipids are higher and six of the same lipid derivatives are lower in acquired obesity. Finally, in adipose tissue, but not in skeletal muscle, mitochondrial downregulation and upregulated inflammation are associated with a fatty liver, insulin resistance, and dyslipidemia, suggesting that adipose tissue dominates in acquired obesity.

Effects of liraglutide on the metabolism of triglyceride-rich lipoproteins in type 2 diabetes.

AIM: To elucidate the impact of liraglutide on the kinetics of apolipoprotein (apo)B48- and apoB100-containing triglyceride-rich lipoproteins in subjects with type 2 diabetes (T2D) after a single fat-rich meal. MATERIALS AND METHODS: Subjects with T2D were included in a study to investigate postprandial apoB48 and apoB100 metabolism before and after 16 weeks on l.8 mg/day liraglutide (n = 14) or placebo (n = 4). Stable isotope tracer and compartmental modelling techniques were used to determine the impact of liraglutide on chylomicron and very low-density lipoprotein (VLDL) production and clearance after a single fat-rich meal. RESULTS: Liraglutide reduced apoB48 synthesis in chylomicrons by 60% (p < .0001) and increased the triglyceride/apoB48 ratio (i.e. the size) of chylomicrons (p < .001). Direct clearance of chylomicrons, a quantitatively significant pathway pretreatment, decreased by 90% on liraglutide (p < .001). Liraglutide also reduced VLDL1 -triglyceride secretion (p = .017) in parallel with reduced liver fat. Chylomicron-apoB48 production and particle size were related to insulin sensitivity (p = .015 and p < .001, respectively), but these associations were perturbed by liraglutide. CONCLUSIONS: In a physiologically relevant setting that mirrored regular feeding in subjects with T2D, liraglutide promoted potentially beneficial changes on postprandial apoB48 metabolism. Using our data in an integrated metabolic model, we describe how the action of liraglutide in T2D on chylomicron and VLDL kinetics could lead to decreased generation of remnant lipoproteins.

Effects of Evolocumab on the Postprandial Kinetics of Apo (Apolipoprotein) B100- and B48-Containing Lipoproteins in Subjects With Type 2 Diabetes.

OBJECTIVE: Increased risk of atherosclerotic cardiovascular disease in subjects with type 2 diabetes is linked to elevated levels of triglyceride-rich lipoproteins and their remnants. The metabolic effects of PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors on this dyslipidemia were investigated using stable-isotope-labeled tracers. Approach and Results: Triglyceride transport and the metabolism of apos (apolipoproteins) B48, B100, C-III, and E after a fat-rich meal were investigated before and on evolocumab treatment in 13 subjects with type 2 diabetes. Kinetic parameters were determined for the following: apoB48 in chylomicrons; triglyceride in VLDL1 (very low-density lipoprotein) and VLDL2; and apoB100 in VLDL1, VLDL2, IDL (intermediate-density lipoprotein), and LDL (low-density lipoprotein). Evolocumab did not alter the kinetics of apoB48 in chylomicrons or apoB100 or triglyceride in VLDL1. In contrast, the fractional catabolic rates of VLDL2-apoB100 and VLDL2-triglyceride were both increased by about 45%, which led to a 28% fall in the VLDL2 plasma level. LDL-apoB100 was markedly reduced by evolocumab, which was linked to metabolic heterogeneity in this fraction. Evolocumab increased clearance of the more rapidly metabolized LDL by 61% and decreased production of the more slowly cleared LDL by 75%. ApoC-III kinetics were not altered by evolocumab, but the apoE fractional catabolic rates increased by 45% and the apoE plasma level fell by 33%. The apoE fractional catabolic rates was associated with the decrease in VLDL2- and IDL-apoB100 concentrations. CONCLUSIONS: Evolocumab had only minor effects on lipoproteins that are involved in triglyceride transport (chylomicrons and VLDL1) but, in contrast, had a profound impact on lipoproteins that carry cholesterol (VLDL2, IDL, LDL). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02948777.

The PNPLA3-I148M Variant Confers an Antiatherogenic Lipid Profile in Insulin-resistant Patients.

CONTEXT: The I148M (rs738409-G) variant in PNPLA3 increases liver fat content but may be protective against cardiovascular disease. Insulin resistance (IR) amplifies the effect of PNPLA3-I148M on liver fat. OBJECTIVE: To study whether PNPLA3-I148M confers an antihyperlipidemic effect in insulin-resistant patients. DESIGN: Cross-sectional study comparing the impact of PNPLA3-I148M on plasma lipids and lipoproteins in 2 cohorts, both divided into groups based on rs738409-G allele carrier status and median HOMA-IR. SETTING: Tertiary referral center. PATIENTS: A total of 298 obese patients who underwent a liver biopsy during bariatric surgery (bariatric cohort: age 49 ±â€…9 years, body mass index [BMI] 43.2 ±â€…6.8 kg/m2), and 345 less obese volunteers in whom liver fat was measured by proton magnetic resonance spectroscopy (nonbariatric cohort: age 45 ±â€…14 years, BMI 29.7 ±â€…5.7 kg/m2). MAIN OUTCOME MEASURES: Nuclear magnetic resonance profiling of plasma lipids, lipoprotein particle subclasses and their composition. RESULTS: In both cohorts, individuals carrying the PNPLA3-I148M variant had significantly higher liver fat content than noncarriers. In insulin-resistant and homozygous carriers, PNPLA3-I148M exerted a distinct antihyperlipidemic effect with decreased very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles and their constituents, and increased high-density lipoprotein particles and their constituents, compared with noncarriers. VLDL particles were smaller and LDL particles larger in PNPLA3-I148M carriers. These changes were geometrically opposite to those due to IR. PNPLA3-I148M did not have a measurable effect in patients with lower IR, and its effect was smaller albeit still significant in the less obese than in the obese cohort. CONCLUSIONS: PNPLA3-I148M confers an antiatherogenic plasma lipid profile particularly in insulin-resistant individuals.

Effects of TM6SF2 E167K on hepatic lipid and very low-density lipoprotein metabolism in humans.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. The transmembrane 6 superfamily member 2 (TM6SF2) E167K genetic variant associates with NAFLD and with reduced plasma triglyceride levels in humans. However, the molecular mechanisms underlying these associations remain unclear. We hypothesized that TM6SF2 E167K affects hepatic very low-density lipoprotein (VLDL) secretion and studied the kinetics of apolipoprotein B100 (apoB100) and triglyceride metabolism in VLDL in homozygous subjects. In 10 homozygote TM6SF2 E167K carriers and 10 matched controls, we employed stable-isotope tracer and compartmental modeling techniques to determine apoB100 and triglyceride kinetics in the 2 major VLDL subfractions: large triglyceride-rich VLDL1 and smaller, less triglyceride-rich VLDL2. VLDL1-apoB100 production was markedly reduced in homozygote TM6SF2 E167K carriers compared with controls. Likewise, VLDL1-triglyceride production was 35% lower in the TM6SF2 E167K carriers. In contrast, the direct production rates for VLDL2-apoB100 and triglyceride were not different between carriers and controls. In conclusion, the TM6SF2 E167K genetic variant was linked to a specific reduction in hepatic secretion of large triglyceride-rich VLDL1. The impaired secretion of VLDL1 explains the reduced plasma triglyceride concentration and provides a basis for understanding the lower risk of cardiovascular disease associated with the TM6SF2 E167K genetic variant.