| 1. |
- Drevinge, Christina, 1983, et al.
(författare)
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Perilipin 5 is protective in the ischemic heart
- 2016
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 219, s. 446-454
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Tidskriftsartikel (refereegranskat)abstract
- Background: Myocardial ischemia is associated with alterations in cardiac metabolism, resulting in decreased fatty acid oxidation and increased lipid accumulation. Here we investigate how myocardial lipid content and dynamics affect the function of the ischemic heart, and focus on the role of the lipid droplet protein perilipin 5 (Plin5) in the pathophysiology of myocardial ischemia. Methods and results: We generated Plin5(-/-) mice and found that Plin5 deficiency dramatically reduced the triglyceride content in the heart. Under normal conditions, Plin5(-/-) mice maintained a close to normal heart function by decreasing fatty acid uptake and increasing glucose uptake, thus preserving the energy balance. However, during stress or myocardial ischemia, Plin5 deficiency resulted in myocardial reduced substrate availability, severely reduced heart function and increased mortality. Importantly, analysis of a human cohort with suspected coronary artery disease showed that a common noncoding polymorphism, rs884164, decreases the cardiac expression of PLIN5 and is associated with reduced heart function following myocardial ischemia, indicating a role for Plin5 in cardiac dysfunction. Conclusion: Our findings indicate that Plin5 deficiency alters cardiac lipid metabolism and associates with reduced survival following myocardial ischemia, suggesting that Plin5 plays a beneficial role in the heart following ischemia. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.
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| 2. |
- Huang-Doran, Isabel, et al.
(författare)
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Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.
- 2016
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Ingår i: JCI insight. - 2379-3708. ; 1:17
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Tidskriftsartikel (refereegranskat)abstract
- Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome.
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| 3. |
- Mardinoglu, Adil, 1982, et al.
(författare)
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An Integrated Understanding of the Rapid Metabolic Benefits of a Carbohydrate-Restricted Diet on Hepatic Steatosis in Humans
- 2018
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 27:3
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Bailetti, D., et al.
(författare)
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ANGPTL4 gene E40K variation protects against obesity-associated dyslipidemia in participants with obesity
- 2019
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Ingår i: Obesity Science & Practice. - : Wiley. - 2055-2238. ; 5:1, s. 83-90
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Tidskriftsartikel (refereegranskat)abstract
- Objective ANGPTL4 inhibits lipoprotein lipase in adipose tissue, regulating plasma triglycerides levels. In persons with obesity plasma ANGPTL4 levels have been positively correlated with body fat mass, TG levels and low HDL. A loss-of-function E40K mutation in ANGPTL4 prevents LPL inhibition, resulting in lower TGs and higher HDLc in the general population. Since obesity determines metabolic alterations and consequently is a major risk factor for cardiovascular disease, the aim was to explore if obesity-related metabolic abnormalities are modified by the ANGPTL4-E40K mutation. Methods ANGPTL4-E40K was screened in 1206 Italian participants, of which 863 (71.5%) with obesity. All subjects without diabetes underwent OGTT with calculation of indices of insulin-sensitivity. Results Participants with obesity carrying the E40K variant had significantly lower TG (p = 0.001) and higher HDLc levels (p = 0.024). Also in the whole population low TGs and high HDLc were confirmed in E40K carriers. In the obese subpopulation it was observed that almost all E40K carriers were within the lowest quartile of TGs (p = 1.1 x 10(-9)). E40K had no substantial effect of on glucose metabolism. Finally, none of the obese E40K carriers had T2D, and together with the favourable lipid profile, they resemble a metabolically healthy obese (MHO) phenotype, compared to 38% of E40E wild-type obese that had diabetes and/or dyslipidaemia (p = 0.0106). Conclusions In participants with obesity the ANGPTL4-E40K variant protects against dyslipidemia. The phenotype of obese E40K carriers is that of a patient with obesity without metabolic alterations, similar to the phenotype described as metabolic healthy obesity.
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| 5. |
- Björnson, Elias, 1988, et al.
(författare)
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Stratification of Hepatocellular Carcinoma Patients Based on Acetate Utilization
- 2015
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 13:9, s. 2014-2026
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Tidskriftsartikel (refereegranskat)abstract
- Hepatocellular carcinoma (HCC) is a deadly form of liver cancer that is increasingly prevalent. We analyzed global gene expression profiling of 361 HCC tumors and 49 adjacent noncancerous liver samples by means of combinatorial network-based analysis. We investigated the correlation between transcriptome and proteome of HCC and reconstructed a functional genome-scale metabolic model (GEM) for HCC. We identified fundamental metabolic processes required for cell proliferation using the network centric view provided by the GEM. Our analysis revealed tight regulation of fatty acid biosynthesis (FAB) and highly significant deregulation of fatty acid oxidation in HCC. We predicted mitochondrial acetate as an emerging substrate for FAB through upregulation of mitochondrial acetyl-CoA synthetase (ACSS1) in HCC. We analyzed heterogeneous expression of ACSS1 and ACSS2 between HCC patients stratified by high and low ACSS1 and ACSS2 expression and revealed that ACSS1 is associated with tumor growth and malignancy under hypoxic conditions in human HCC.
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| 6. |
- Burza, Maria Antonella, 1980, et al.
(författare)
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DEPDC5 variants increase fibrosis progression in Europeans with chronic HCV infection.
- 2016
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Ingår i: Hepatology (Baltimore, Md.). - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 63:2, s. 418-427
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Tidskriftsartikel (refereegranskat)abstract
- Chronic hepatitis C virus (HCV) infection may progress to cirrhosis and hepatocellular carcinoma (HCC). Recently, two genetic variants, DEPDC5 rs1012068 and MICA rs2596542, were associated with the onset of HCC in Asian subjects with chronic HCV infection. The aim of the present study was to analyze whether DEPDC5 and MICA genetic variants were associated with liver disease progression in Europeans with chronic HCV infection. In a Northern Italian discovery cohort (n=477), neither DEPDC5 rs1012068 nor MICA rs2596542 were associated with HCC (n=150). However, DEPDC5 rs1012068 was independently associated with cirrhosis (n=300; p=0.049). The association of rs1012068 with moderate-severe fibrosis was confirmed in an independent cross-sectional German cohort (n=415; p=0.006). Furthermore, DEPDC5 rs1012068 predicted faster fibrosis progression in a prospective cohort (n=247; p=0.027). Next, we examined the distribution of non-synonymous DEPDC5 variants in the overall cross-sectional cohort (n=912). The presence of at least one variant increased the risk of moderate/severe fibrosis by 54% (p=0.040). To understand the molecular mechanism underlying the genetic association of DEPDC5 variants with fibrosis progression, we performed in vitro studies on immortalized hepatic stellate cells (LX-2). In these cells, down-regulation of DEPDC5 resulted in increased expression of β-catenin and production of its target matrix metallopeptidase 2 (MMP2), a secreted enzyme involved in fibrosis progression.
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| 7. |
- Caddeo, Andrea, et al.
(författare)
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MBOAT7 is anchored to endomembranes by six transmembrane domains.
- 2019
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Ingår i: Journal of structural biology. - : Elsevier BV. - 1095-8657 .- 1047-8477. ; 206:3, s. 349-360
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Tidskriftsartikel (refereegranskat)abstract
- Membrane bound O-acyltransferase domain- containing 7 (MBOAT7, also known as LPIAT1) is a protein involved in the acyl chain remodeling of phospholipids via the Lands' cycle. The MBOAT7 is a susceptibility risk genetic locus for non-alcoholic fatty liver disease (NAFLD) and mental retardation. Although it has been shown that MBOAT7 is associated to membranes, the MBOAT7 topology remains unknown. To solve the topological organization of MBOAT7, we performed: A) solubilization of the total membrane fraction of cells overexpressing the recombinant MBOAT7-V5, which revealed MBOAT7 is an integral protein strongly attached to endomembranes; B) in silico analysis by using 22 computational methods, which predicted the number and localization of transmembrane domains of MBOAT7 with a range between 5 and 12; C) in vitro analysis of living cells transfected with GFP-tagged MBOAT7 full length and truncated forms, using a combination of Western Blotting, co-immunofluorescence and Fluorescence Protease Protection (FPP) assay; D) in vitro analysis of living cells transfected with FLAG-tagged MBOAT7 full length forms, using a combination of Western Blotting, selective membrane permeabilization followed by indirect immunofluorescence. All together, these data revealed that MBOAT7 is a multispanning transmembrane protein with six transmembrane domains. Based on our model, the predicted catalytic dyad of the protein, composed of the conserved asparagine in position 321 (Asn-321) and the preserved histidine in position 356 (His-356), has a lumenal localization. These data are compatible with the role of MBOAT7 in remodeling the acyl chain composition of endomembranes.
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| 8. |
- Caddeo, Andrea, et al.
(författare)
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Molecular analysis of three known and one novel LPL variants in patients with type I hyperlipoproteinemia.
- 2018
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Ingår i: Nutrition, metabolism, and cardiovascular diseases : NMCD. - : Elsevier BV. - 1590-3729 .- 0939-4753. ; 28, s. 158-164
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Tidskriftsartikel (refereegranskat)abstract
- Type I hyperlipoproteinemia, also known as familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disorder caused by variants in LPL, APOC2, APOA5, LMF1 or GPIHBP1 genes. The aim of this study was to identify novel variants in the LPL gene causing lipoprotein lipase deficiency and to understand the molecular mechanisms.A total of 3 individuals with severe hypertriglyceridemia and recurrent pancreatitis were selected from the Lipid Clinic at Sahlgrenska University Hospital and LPL was sequenced. Invitro experiments were performed in human embryonic kidney 293T/17 (HEK293T/17) cells transiently transfected with wild type or mutant LPL plasmids. Cell lysates and media were used to analyze LPL synthesis and secretion. Media were used to measure LPL activity. Patient 1 was compound heterozygous for three known variants: c.337T>C (W113R), c.644G>A (G215E) and c.1211T>G (M404R); patient 2 was heterozygous for the known variant c.658A>C (S220R) while patient 3 was homozygous for a novel variant in the exon 5 c.679G>T (V227F). All the LPL variants identified were loss-of-function variants and resulted in a substantial reduction in the secretion of LPL protein.We characterized at the molecular level three known and one novel LPL variants causing type I hyperlipoproteinemia showing that all these variants are pathogenic.
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| 9. |
- Carlsson, Lena M S, 1957, et al.
(författare)
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The incidence of albuminuria after bariatric surgery and usual care in swedish obese subjects (SOS): a prospective controlled intervention trial.
- 2015
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 39:1, s. 169-175
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Tidskriftsartikel (refereegranskat)abstract
- Background:Obesity is associated with increased risk of chronic kidney disease and albuminuria is a predictor of renal impairment. Bariatric surgery reduces body weight in obese subjects, but it is not known whether surgery can prevent development of albuminuria. This study aims to determine the long-term effect of bariatric surgery on the incidence of albuminuria.Subjects:The Swedish Obese Subjects study is a non-randomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden. Between 1 September 1987 and 31 January 2001, 2010 participants who underwent bariatric surgery and 2037 controls were recruited. Inclusion criteria were age 37-60 years and BMI⩾34 in men and BMI⩾38 in women. In this analysis, we included 1498 patients in the surgery group and 1610 controls without albuminuria at baseline. Patients in the bariatric surgery group underwent banding (18%), vertical banded gastroplasty (69%) or gastric bypass (13%); controls received usual obesity care. Date of analysis was 1 January 2011. Median follow-up was 10 years, and the rates of follow-up were 87%, 74 and 52% at 2, 10 and 15 years, respectively. The main outcome of this report is incidence of albuminuria (defined as urinary albumin excretion >30mg per 24h) over up to 15 years.Results:During the follow-up, albuminuria developed in 246 participants in the control group and in 126 in the bariatric surgery group, corresponding to incidence rates of 20.4 and 9.4 per 1000 person years, respectively (adjusted hazard ratio, 0.37; 95% confidence interval, 0.30-0.47; P<0.001). The expected number of surgeries needed to prevent the development of albuminuria in one patient at 10 years was nine.Conclusions:Bariatric surgery is associated with reduced incidence of albuminuria compared with usual obesity care.International Journal of Obesity advance online publication, 10 June 2014; doi:10.1038/ijo.2014.72.
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| 10. |
- Colica, C., et al.
(författare)
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Dietary Patterns and Fractures risk in the elderly
- 2017
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:Although the role of dietary factors in the prevention of bone loss and fractures has been investigated in many studies, few studies have examined the association between dietary patterns and total body bone density. Our aim was to determine the relations between dietary patterns and whole-body bone mineral density (WB-BMD) and the association between dietary patterns, fractures, and multiple fractures in the elderly. Methods:This cross-sectional study included 177 individuals aged >= 65 years. A dual X-ray absorptiometry scan was performed to measure BMD. Dietary patterns were ascertained by a combination of dietary intake assessment and principal components analysis. Results:Only three dietary patterns correlated with whole-body bone density. The multivariate-adjusted mean bone density across tertiles of these dietary patterns showed that the highest tertile of both the patterns 1 and 2 had a significantly higher bone density than the lowest tertile (pattern 1:1.021 +/- 0.01 and 1.070 +/- 0.01 g/cm(2) for T1 and T3, respectively; p = 0.043; pattern 2:1.023 +/- 0.01, and 1.081 +/- 0.01 g/cm(2) for T1 and T3, respectively; p = 0.003). We also find significant gender difference in these results. The highest adherence to the dietary pattern 5 was associated with decreased odds of having fractures (OR = 0.20, p = 0.009), and adherence to the pattern 1 was negatively associated with multiple fractures. Conclusion:A high adherence to the dietary pattern 1 (high intake of grains, fish and olive oil) was associated with a high BMD and a low number of fractures. The highest adherence to the dietary pattern 5 (legumes and wine) was associated with decreased odds of having fractures. Our finding would suggest a potential bone-preserving properties of specific dietary patterns in the elderly.
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