المؤلفون: Qadri, Sami, Vartiainen, Emilia, Lahelma, Mari, Porthan, Kimmo, Tang, An, Idilman, Ilkay S, Runge, Jurgen H, Juuti, Anne, Penttilä, Anne K, Dabek, Juhani, Lehtimäki, Tiina E, Seppänen, Wenla, Arola, Johanna, Arkkila, Perttu, Stoker, Jaap, Karcaaltincaba, Musturay, Pavlides, Michael, Loomba, Rohit, Sirlin, Claude B, Tukiainen, Taru, Yki-Järvinen, Hannele

المصدر: JHEP Reports. 6(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Chronic Liver Disease and Cirrhosis, Liver Disease, Digestive Diseases, Oral and gastrointestinal, Fatty liver, Metabolic dysfunction-associated steatotic liver disease, Magnetic resonance imaging, Magnetic resonance spectroscopy, Biopsy, Histology, Hepatocytes, Pathologists, Triglycerides, Transcriptome, Systematic review, Meta-analysis, Clinical sciences

الوصف: Background & aimsPathologists quantify liver steatosis as the fraction of lipid droplet-containing hepatocytes out of all hepatocytes, whereas the magnetic resonance-determined proton density fat fraction (PDFF) reflects the tissue triacylglycerol concentration. We investigated the linearity, agreement, and correspondence thresholds between histological steatosis and PDFF across the full clinical spectrum of liver fat content associated with non-alcoholic fatty liver disease.MethodsUsing individual patient-level measurements, we conducted a systematic review and meta-analysis of studies comparing histological steatosis with PDFF determined by magnetic resonance spectroscopy or imaging in adults with suspected non-alcoholic fatty liver disease. Linearity was assessed by meta-analysis of correlation coefficients and by linear mixed modelling of pooled data, agreement by Bland-Altman analysis, and thresholds by receiver operating characteristic analysis. To explain observed differences between the methods, we used RNA-seq to determine the fraction of hepatocytes in human liver biopsies.ResultsEligible studies numbered 9 (N = 597). The relationship between PDFF and histology was predominantly linear (r = 0.85 [95% CI, 0.80-0.89]), and their values approximately coincided at 5% steatosis. Above 5% and towards higher levels of steatosis, absolute values of the methods diverged markedly, with histology exceeding PDFF by up to 3.4-fold. On average, 100% histological steatosis corresponded to a PDFF of 33.0% (29.5-36.7%). Targeting at a specificity of 90%, optimal PDFF thresholds to predict histological steatosis grades were ≥5.75% for ≥S1, ≥15.50% for ≥S2, and ≥21.35% for S3. Hepatocytes comprised 58 ± 5% of liver cells, which may partly explain the lower values of PDFF vs. histology.ConclusionsHistological steatosis and PDFF have non-perfect linearity and fundamentally different scales of measurement. Liver fat values obtained using these methods may be rendered comparable by conversion equations or threshold values.Impact and implicationsMagnetic resonance-proton density fat fraction (PDFF) is increasingly being used to measure liver fat in place of the invasive liver biopsy. Understanding the relationship between PDFF and histological steatosis fraction is important for preventing misjudgement of clinical status or treatment effects in patient care. Our analysis revealed that histological steatosis fraction is often significantly higher than PDFF, and their association varies across the spectrum of fatty liver severity. These findings are particularly important for physicians and clinical researchers, who may use these data to interpret PDFF measurements in the context of histologically evaluated liver fat content.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8vr8h6b9Test

المؤلفون: Qadri, Sami, Ahlholm, Noora, Lonsmann, Ida, Pellegrini, Paola, Poikola, Anni, Luukkonen, Panu K., Porthan, Kimmo, Juuti, Anne, Sammalkorpi, Henna, Penttilä, Anne K., D´Ambrosio, Roberta, Soardo, Giorgio, Leeming, Diana J., Karsdal, Morten, Arola, Johanna, Kechagias, Stergios, 1969, Pelusi, Serena, Ekstedt, Mattias, 1976, Valenti, Luca, Hagström, Hannes, Yki-Järvinen, Hannele

المصدر: Journal of Clinical Endocrinology and Metabolism. 107(5):e2008-e2020

مصطلحات موضوعية: nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, fibrosis, cirrhosis, biomarkers, obesity

الوصف: Context: Guidelines recommend blood-based fibrosis biomarkers to identify advanced nonalcoholic fatty liver disease (NAFLD), which is particularly prevalent in patients with obesity. Objective: To study whether the degree of obesity affects the performance of liver fibrosis biomarkers in NAFLD. Design: Cross-sectional cohort study comparing simple fibrosis scores [Fibrosis-4 Index (FIB-4); NAFLD Fibrosis Score (NFS); aspartate aminotransferase to platelet ratio index; BARD (body mass index, aspartate-to-alanine aminotransferase ratio, diabetes); Hepamet Fibrosis Score (HFS)] and newer scores incorporating neo-epitope biomarkers PRO-C3 (ADAPT, FIBC3) or cytokeratin 18 (MACK-3). Setting: Tertiary referral center. Patients: We recruited overweight/obese patients from endocrinology (n = 307) and hepatology (n = 71) clinics undergoing a liver biopsy [median body mass index (BMI) 40.3 (interquartile range 36.0-44.7) kg/m(2)]. Additionally, we studied 859 less obese patients with biopsy-proven NAFLD to derive BMI-adjusted cutoffs for NFS. Main Outcome Measures: Biomarker area under the receiver operating characteristic (AUROC), sensitivity, specificity, and predictive values to identify histological stage >= F3 fibrosis or nonalcoholic steatohepatitis with >= F2 fibrosis [fibrotic nonalcoholic steatohepatitis (NASH)]. Results: The scores with an AUROC >= 0.85 to identify >= F3 fibrosis were ADAPT, FIB-4, FIBC3, and HFS. For fibrotic NASH, the best predictors were MACK-3 and ADAPT. The specificities of NFS, BARD, and FIBC3 deteriorated as a function of BMI. We derived and validated new cutoffs for NFS to rule in/out >= F3 fibrosis in groups with BM Is <30.0, 30.0 to 39.9, and >= 40.0 kg/m(2). This optimized its performance at all levels of BMI. Sequentially combining FIB-4 with ADAPT or FIBC3 increased specificity to diagnose >= F3 fibrosis. Conclusions: In obese patients, the best-performing fibrosis biomarkers are ADAPT and the inexpensive FIB-4, which are unaffected by BMI. The widely used NFS loses specificity in obese individuals, which may be corrected with BMI-adjusted cutoffs.

وصف الملف: electronic

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-183250Test
https://doi.org/10.1210/clinem/dgab933Test
https://liu.diva-portal.org/smash/get/diva2:1642182/FULLTEXT01.pdfTest

المؤلفون: Luukkonen, Panu K., Qadri, Sami, Ahlholm, Noora, Porthan, Kimmo, Männistö, Ville, Sammalkorpi, Henna, Penttilä, Anne K., Hakkarainen, Antti, Lehtimäki, Tiina E., Gaggini, Melania, Gastaldelli, Amalia, Ala-Korpela, Mika, Orho-Melander, Marju, Arola, Johanna, Juuti, Anne, Pihlajamäki, Jussi, Hodson, Leanne, Yki-Järvinen, Hannele

المصدر: Journal of Hepatology EpiHealth: Epidemiology for Health EXODIAB: Excellence of Diabetes Research in Sweden. 76(3):526-535

مصطلحات موضوعية: adipose tissue lipolysis, de novo lipogenesis, hepatic mitochondrial redox state, HSD17B13, insulin resistance, MARC1, MBOAT7, metabolomics, PNPLA3, TM6SF2, Medicin och hälsovetenskap, Klinisk medicin, Endokrinologi och diabetes, Medical and Health Sciences, Clinical Medicine, Endocrinology and Diabetes

الوصف: 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 β-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum β-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.

الوصول الحر: https://lup.lub.lu.se/record/6eafb112-5323-4cc8-9779-09d8d0b0b232Test
http://dx.doi.org/10.1016/j.jhep.2021.10.013Test

المؤلفون: Luukkonen, Panu K., Sakuma, Ikki, Gaspar, Rafael C., Mooring, Meghan, Nasiri, Ali, Kahn, Mario, Zhang, Xian Man, Zhang, Dongyan, Sammalkorpi, Henna, Penttilä, Anne K., Orho-Melander, Marju, Arola, Johanna, Juuti, Anne, Zhang, Xuchen, Yimlamai, Dean, Yki-Järvinen, Hannele, Petersen, Kitt Falk, Shulman, Gerald I.

المصدر: Proceedings of the National Academy of Sciences of the United States of America EpiHealth: Epidemiology for Health EXODIAB: Excellence of Diabetes Research in Sweden. 120(4)

مصطلحات موضوعية: hydroxysteroid 17-beta dehydrogenase 13, liver fibrosis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, pyrimidines, Medicin och hälsovetenskap, Klinisk medicin, Gastroenterologi, Medical and Health Sciences, Clinical Medicine, Gastroenterology and Hepatology

الوصف: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. A common variant in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13, rs72613567-A) is associated with a reduced risk of fibrosis in NAFLD, but the underlying mechanism(s) remains unclear. We investigated the effects of this variant in the human liver and in Hsd17b13 knockdown in mice by using a state-of-the-art metabolomics approach. We demonstrate that protection against liver fibrosis conferred by the HSD17B13 rs72613567-A variant in humans and by the Hsd17b13 knockdown in mice is associated with decreased pyrimidine catabolism at the level of dihydropyrimidine dehydrogenase. Furthermore, we show that hepatic pyrimidines are depleted in two distinct mouse models of NAFLD and that inhibition of pyrimidine catabolism by gimeracil phenocopies the HSD17B13-induced protection against liver fibrosis. Our data suggest pyrimidine catabolism as a therapeutic target against the development of liver fibrosis in NAFLD.

الوصول الحر: https://lup.lub.lu.se/record/9b87d22f-9e1c-4cf8-8fe2-9fea2c950248Test
http://dx.doi.org/10.1073/pnas.2217543120Test

المؤلفون: Qadri, Sami, Lallukka-Brück, Susanna, Luukkonen, Panu K., Zhou, You, Gastaldelli, Amalia, Orho-Melander, Marju, Sammalkorpi, Henna, Juuti, Anne, Penttilä, Anne K., Perttilä, Julia, Hakkarainen, Antti, Lehtimäki, Tiina E., Oresic, Matej, 1967, Hyötyläinen, Tuulia, 1971, Hodson, Leanne, Olkkonen, Vesa M., Yki-Järvinen, Hannele

المصدر: Liver international (Print). 40(9):2128-2138

مصطلحات موضوعية: Adipose tissue, fatty acids, lipidomics, lipolysis, non-alcoholic fatty liver disease, triglycerides

الوصف: BACKGROUND & AIMS: The I148M variant in PNPLA3 is the major genetic risk factor for non-alcoholic fatty liver disease (NAFLD). The liver is enriched with polyunsaturated triglycerides (PUFA-TGs) in PNPLA3-I148M carriers. Gene expression data indicate that PNPLA3 is liver-specific in humans, but whether it functions in adipose tissue (AT) is unknown. We investigated whether PNPLA3-I148M modifies AT metabolism in human NAFLD.METHODS: Profiling of the AT lipidome and fasting serum non-esterified fatty acid (NEFA) composition were conducted in 125 volunteers (PNPLA3148MM/MI , n=63; PNPLA3148II , n=62). AT fatty acid composition was determined in 50 volunteers homozygous for the variant (PNPLA3148MM , n=25) or lacking the variant (PNPLA3148II , n=25). Whole-body insulin sensitivity of lipolysis was determined using [2 H5 ]glycerol, and PNPLA3 mRNA and protein levels were measured in subcutaneous AT and liver biopsies in a subset of the volunteers.RESULTS: PUFA-TGs were significantly increased in AT in carriers versus non-carriers of PNPLA3-I148M. The variant did not alter the rate of lipolysis or the composition of fasting serum NEFAs. PNPLA3 mRNA was 33-fold higher in the liver than in AT (p<0.0001). In contrast, PNPLA3 protein levels per tissue protein were 3-fold higher in AT than the liver (p<0.0001) and 9-fold higher when related to whole-body AT and liver tissue masses (p<0.0001).CONCLUSIONS: Contrary to previous assumptions, PNPLA3 is highly abundant in AT. PNPLA3-I148M locally remodels AT TGs to become polyunsaturated as it does in the liver, without affecting lipolysis or composition of serum NEFAs. Changes in AT metabolism do not contribute to NAFLD in PNPLA3-I148M carriers.

وصف الملف: print

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-81765Test
https://doi.org/10.1111/liv.14507Test

المؤلفون: Luiken, Ina, Eisenmann, Stephan, Garbe, Jakob, Sternby, Hanna, Verdonk, Robert C., Dimova, Alexandra, Ignatavicius, Povilas, Ilzarbe, Lucas, Koiva, Peeter, Penttilä, Anne K., Regnér, Sara, Dober, Johannes, Wohlgemuth, Walter A., Brill, Richard, Michl, Patrick, Rosendahl, Jonas, Damm, Marko

المصدر: PLoS ONE. 17(2 February)

مصطلحات موضوعية: Medicin och hälsovetenskap, Klinisk medicin, Kirurgi, Medical and Health Sciences, Clinical Medicine, Surgery

الوصف: Background Respiratory failure worsens the outcome of acute pancreatitis (AP) and underlying factors might be early detectable. Aims To evaluate the prevalence and prognostic relevance of early pleuropulmonary pathologies and pre-existing chronic lung diseases (CLD) in AP patients. Methods Multicentre retrospective cohort study. Caudal sections of the thorax derived from abdominal contrast enhanced computed tomography (CECT) performed in the early phase of AP were assessed. Independent predictors of severe AP were identified by binary logistic regression analysis. A one-year survival analysis using Kaplan-Meier curves and log rank test was performed. Results 358 patients were analysed, finding pleuropulmonary pathologies in 81%. CECTs were performed with a median of 2 days (IQR 1–3) after admission. Multivariable analysis identified moderate to severe or bilateral pleural effusions (PEs) (OR = 4.16, 95%CI 2.05–8.45, p<0.001) and pre-existing CLD (OR = 2.93, 95%CI 1.17–7.32, p = 0.022) as independent predictors of severe AP. Log rank test showed a significantly worse one-year survival in patients with bilateral compared to unilateral PEs in a subgroup. Conclusions Increasing awareness of the prognostic impact of large and bilateral PEs and pre-existing CLD could facilitate the identification of patients at high risk for severe AP in the early phase and thus improve their prognosis.

الوصول الحر: https://lup.lub.lu.se/record/e1886ba5-d035-45ed-a80a-3371cf237c11Test
http://dx.doi.org/10.1371/journal.pone.0263739Test

المؤلفون: Lahelma, Mari, Luukkonen, Panu K., Qadri, Sami, Ahlholm, Noora, Lallukka-Brück, Susanna, Porthan, Kimmo, Juuti, Anne, Sammalkorpi, Henna, Penttilä, Anne K., Arola, Johanna, Orho-Melander, Marju, Yki-Järvinen, Hannele

المصدر: Nutrients EpiHealth: Epidemiology for Health EXODIAB: Excellence of Diabetes Research in Sweden. 13(1)

مصطلحات موضوعية: Diet, Glucose, Insulin, Physical activity, Stress, Medicin och hälsovetenskap, Klinisk medicin, Gastroenterologi, Medical and Health Sciences, Clinical Medicine, Gastroenterology and Hepatology, Hälsovetenskap, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Health Sciences, Public Health, Global Health, Social Medicine and Epidemiology

الوصف: Only some individuals with obesity develop liver fibrosis due to non-alcoholic fatty liver disease (NAFLD-fibrosis). We determined whether detailed assessment of lifestyle factors in addition to physical, biochemical and genetic factors helps in identification of these patients. A total of 100 patients with obesity (mean BMI 40.0 ± 0.6 kg/m2 ) referred for bariatric surgery at the Helsinki University Hospital underwent a liver biopsy to evaluate liver histology. Physical activity was determined by accelerometer recordings and by the Modifiable Activity Questionnaire, diet by the FINRISK Food Frequency Questionnaire, and other lifestyle factors, such as sleep patterns and smoking, by face-to-face interviews. Physical and biochemical parameters and genetic risk score (GRS based on variants in PNPLA3, TM6SF2, MBOAT7 and HSD17B13) were measured. Of all participants 49% had NAFLD-fibrosis. Independent predictors of NAFLD-fibrosis were low moderate-to-vigorous physical activity, high red meat intake, low carbohydrate intake, smoking, HbA1c, triglycerides and GRS. A model including these factors (areas under the receiver operating characteristics curve (AUROC) 0.90 (95% CI 0.84–0.96)) identified NAFLD-fibrosis significantly more accurately than a model including all but lifestyle factors (AUROC 0.82 (95% CI 0.73–0.91)) or models including lifestyle, physical and biochemical, or genetic factors alone. Assessment of lifestyle parameters in addition to physical, biochemical and genetic factors helps to identify obese patients with NAFLD-fibrosis.

الوصول الحر: https://lup.lub.lu.se/record/6ea09214-dd4b-44d9-8016-b61b2321ec06Test
http://dx.doi.org/10.3390/nu13010169Test

المؤلفون: Heinonen, Sini, Saarinen, Tuure, Meriläinen, Sanna, Sammalkorpi, Henna, Penttilä, Anne K., Koivikko, Minna, Siira, Pertti, Karppinen, Jaro, Säiläkivi, Ulla, Rosengård‐Bärlund, Milla, Koivukangas, Vesa, Pietiläinen, Kirsi H., Juuti, Anne

المصدر: Obesity (19307381); Dec2023, Vol. 31 Issue 12, p2909-2923, 15p

مصطلحات موضوعية: GASTRIC bypass, RANDOMIZED controlled trials, BODY composition, NUTRITION, BODY weight, ANTIHYPERTENSIVE agents

مستخلص: Objective: Although it has been suggested that one‐anastomosis gastric bypass (OAGB) is metabolically superior to the "gold standard," i.e., Roux‐en‐Y gastric bypass (RYGB), there is little robust evidence to prove it. Because this result may arise from the typically longer length of bypassed intestine in OAGB, here, the authors standardized the bypass length in RYGB and OAGB and compared weight loss and metabolic outcomes in a randomized controlled trial. Methods: The authors randomized 121 bariatric patients to RYGB (n = 61) or OAGB (n = 60) in two Finnish University Hospitals and measured weight; body composition; metabolic features (insulin sensitivity, lipids, inflammation, nutrition); and comorbidities before and 6 and 12 months after the operation. Results: Total weight loss was similar in RYGB and OAGB at 6 months (mean: 21.2% [95% CI: 19.4–23.0] vs. 22.8% [95% CI: 21.5–24.1], p = 0.136) and 12 months (25.4% [95% CI: 23.4–27.5] vs. 26.1% [95% CI: 24.2–28.9], p = 0.635). Insulin sensitivity, lipids, and inflammation improved similarly between the groups (p > 0.05). Remission of type 2 diabetes and hypercholesterolemia was marked and similar (p > 0.05) but the use of antihypertensive medications was lower (p = 0.037) and hypertension tended to improve more (p = 0.053) with RYGB versus OAGB at 12 months. Higher rates of vitamin D‐25 deficiency (p < 0.05) and lower D‐25 levels were observed with OAGB versus RYGB throughout the follow‐up (p < 0.001). No differences in adverse effects were observed. Conclusions: RYGB and OAGB were comparable in weight loss, metabolic improvement, remission of diabetes and hypercholesterolemia, and nutrition at 1‐year follow‐up. Vitamin D‐25 deficiency was more prevalent with OAGB, whereas reduction in antihypertensive medications and hypertension was greater with RYGB. There is no need to change the current practices of RYGB in favor of OAGB. [ABSTRACT FROM AUTHOR]

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المؤلفون: Luukkonen, Panu K., Juuti, Anne, Sammalkorpi, Henna, Penttilä, Anne K., Orešič, Matej, Hyötyläinen, Tuulia, Arola, Johanna, Orho-Melander, Marju, Yki-Järvinen, Hannele

المصدر: Journal of Hepatology EpiHealth: Epidemiology for Health EXODIAB: Excellence of Diabetes Research in Sweden. 73(3):725-726

مصطلحات موضوعية: Medicin och hälsovetenskap, Klinisk medicin, Endokrinologi och diabetes, Medical and Health Sciences, Clinical Medicine, Endocrinology and Diabetes

الوصول الحر: https://lup.lub.lu.se/record/e1a5fca3-ff5e-4bef-8fc1-ae3e3e880be1Test
http://dx.doi.org/10.1016/j.jhep.2020.04.021Test

المؤلفون: Luukkonen, Panu K., Qadri, Sami, Lehtimäki, Tiina E., Juuti, Anne, Sammalkorpi, Henna, Penttilä, Anne K., Hakkarainen, Antti, Orho-Melander, Marju, Arola, Johanna, Yki-Järvinen, Hannele

المصدر: The Journal of clinical endocrinology and metabolism EpiHealth: Epidemiology for Health EXODIAB: Excellence of Diabetes Research in Sweden. 106(1):300-315

مصطلحات موضوعية: dyslipidemia, insulin resistance, lipoproteins, metabolic syndrome, non-alcoholic fatty liver disease, patatin-like phospholipase domain containing 3, Medicin och hälsovetenskap, Klinisk medicin, Endokrinologi och diabetes, Medical and Health Sciences, Clinical Medicine, Endocrinology and Diabetes

الوصف: 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 ± 9 years, body mass index [BMI] 43.2 ± 6.8 kg/m2), and 345 less obese volunteers in whom liver fat was measured by proton magnetic resonance spectroscopy (nonbariatric cohort: age 45 ± 14 years, BMI 29.7 ± 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.

الوصول الحر: https://lup.lub.lu.se/record/036003f9-d3d7-4b1e-b617-fd45b253fa4fTest
http://dx.doi.org/10.1210/clinem/dgaa729Test