Seipin is an endoplasmic reticulum (ER) membrane protein implicated in lipid droplet (LD) biogenesis and mutated in severe congenital lipodystrophy (BSCL2). Here, we show that seipin is stably ...associated with nascent ER–LD contacts in human cells, typically via one mobile focal point per LD. Seipin appears critical for such contacts since ER–LD contacts were completely missing or morphologically aberrant in seipin knockout and BSCL2 patient cells. In parallel, LD mobility was increased and protein delivery from the ER to LDs to promote LD growth was decreased. Moreover, while growing LDs normally acquire lipid and protein constituents from the ER, this process was compromised in seipin‐deficient cells. In the absence of seipin, the initial synthesis of neutral lipids from exogenous fatty acid was normal, but fatty acid incorporation into neutral lipids in cells with pre‐existing LDs was impaired. Together, our data suggest that seipin helps to connect newly formed LDs to the ER and that by stabilizing ER–LD contacts seipin facilitates the incorporation of protein and lipid cargo into growing LDs in human cells.
Synopsis
Seipin, mutated in severe congenital lipodystrophy (BSCL2), is an ER–lipid droplet (LD) contact protein that regulates the extent of ER–LD contacts and facilitates incorporation of lipid and protein cargo into maturing LDs.
Seipin deficiency increases the heterogeneity of ER–LD contacts, resulting in completely missing, rudimentary, or very extensive contacts.
Seipin is required during LD formation for the targeting of ER‐derived fatty acid‐activating enzyme ACSL3 to LDs.
An ER‐to‐LD targeting model peptide and a fluorescent fatty acid analog initially reach newly formed LDs, but their subsequent incorporation into LDs is impaired in the absence of seipin.
In seipin deficiency, the fatty acid flux to neutral lipids becomes compromised when LD formation has been initiated.
Seipin, mutated in severe congenital lipodystrophy (BSCL2), is an ER–lipid droplet (LD) contact protein that regulates the extent of ER–LD contacts and facilitates incorporation of lipid and protein cargo into maturing LDs.
Objective:
Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with potentially serious metabolic complications, including diabetes, hypertriglyceridemia, and ...steatohepatitis. Due to their rarity, most clinicians are not familiar with their diagnosis and management. This practice guideline summarizes the diagnosis and management of lipodystrophy syndromes not associated with HIV or injectable drugs.
Participants:
Seventeen participants were nominated by worldwide endocrine societies or selected by the committee as content experts. Funding was via an unrestricted educational grant from Astra Zeneca to the Pediatric Endocrine Society. Meetings were not open to the general public.
Evidence:
A literature review was conducted by the committee. Recommendations of the committee were graded using the system of the American Heart Association. Expert opinion was used when published data were unavailable or scarce.
Consensus Process:
The guideline was drafted by committee members and reviewed, revised, and approved by the entire committee during group meetings. Contributing societies reviewed the document and provided approval.
Conclusions:
Lipodystrophy syndromes are heterogeneous and are diagnosed by clinical phenotype, supplemented by genetic testing in certain forms. Patients with most lipodystrophy syndromes should be screened for diabetes, dyslipidemia, and liver, kidney, and heart disease annually. Diet is essential for the management of metabolic complications of lipodystrophy. Metreleptin therapy is effective for metabolic complications in hypoleptinemic patients with generalized lipodystrophy and selected patients with partial lipodystrophy. Other treatments not specific for lipodystrophy may be helpful as well (eg, metformin for diabetes, and statins or fibrates for hyperlipidemia). Oral estrogens are contraindicated.
Multiple worldwide endocrine societies developed practice guidelines for diagnosis and management of lipodystrophy syndromes based on current evidence.
Current three-dimensional (3D) genome modeling platforms are limited by their inability to account for radial placement of loci in the nucleus. We present Chrom3D, a user-friendly whole-genome 3D ...computational modeling framework that simulates positions of topologically-associated domains (TADs) relative to each other and to the nuclear periphery. Chrom3D integrates chromosome conformation capture (Hi-C) and lamin-associated domain (LAD) datasets to generate structure ensembles that recapitulate radial distributions of TADs detected in single cells. Chrom3D reveals unexpected spatial features of LAD regulation in cells from patients with a laminopathy-causing lamin mutation. Chrom3D is freely available on github.
Mutations in the lamin A/C gene encoding nuclear lamins A and C (lamin A/C) cause familial partial lipodystrophy type 2 (FPLD2) and related lipodystrophy syndromes. These are mainly characterized by ...redistribution of adipose tissue associated with insulin resistance. Several reports suggest that alterations in the extracellular matrix of adipose tissue leading to fibrosis play a role in the pathophysiology of lipodystrophy syndromes. However, the extent of extracellular matrix alterations in FPLD2 remains unknown. We show significantly increased fibrosis and altered expression of genes encoding extracellular matrix proteins in cervical subcutaneous adipose tissue from a human subject with FLPD2. Similar extracellular matrix alterations occur in adipose tissue of transgenic mice expressing an FPLD2-causing human lamin A variant and in cultured fibroblasts from human subjects with FPLD2 and related lipodystrophies. These abnormalities are associated with increased transforming growth factor-β signaling and defects in matrix metalloproteinase 9 activity. Our data demonstrate that lamin A/C gene mutations responsible for FPLD2 and related lipodystrophies are associated with transforming growth factor-β activation and an extracellular matrix imbalance in adipose tissue, suggesting that targeting these alterations could be the basis of novel therapies
Adipose tissue is now recognized for its major role in the control of energy metabolism and insulin sensitivity. We review here the human lipodystrophies, that are rare conditions in which total or ...partial fat loss is associated with severe lipid and glucose abnormalities leading to diabetes with early cardiovascular and hepatic complications. The genetic origin of a number of human lipodystrophies has been recently unraveled, emphasizing the importance of proteins of previously unknown or unexpected functions. Major adipose functions were also illuminated when studying acquired forms of lipodystrophies linked to human immunodeficiency virus-antiretrovirals. Overall, most of the proteins or functions affected by mutations or antiretrovirals result in altered adipogenesis and insulin sensitivity, triglyceride storage and formation of the unique adipocyte lipid droplet, oxidative stress and fat remodeling. Some mutations or antiretrovirals could affect directly (peroxisome proliferator-activated receptor-γ, Akt2) or indirectly (lamin A/C, human immunodeficiency virus-protease inhibitors) adipogenesis, through the transcription factors peroxisome proliferator-activated receptor gamma-γ or sterol regulatory element binding protein 1c, and insulin signaling through Akt2 that controls adipocyte lipolysis. A number of proteins mutated in genetic lipodystrophies are involved in the control of triglyceride synthesis towards the lipid droplet (1-acylglycerol-3-phosphate-O-acyltransferase 2), or its functions (seipin, cell death-inducing DFF45-like effector C, perilipin, caveolin-1, cavin-1). Decreased triglyceride storage leads to adipocyte lipotoxicity, mitochondrial dysfunction and increased oxidative stress, which could also be induced by some thymidine analogue antiretrovirals. This results in production of inflammatory mediators and deregulated release of free fatty acids. Thus, the impaired ability of adipose tissue to safely store triglycerides inside the lipid droplet results in impaired insulin sensitivity and adverted liver, muscles and heart functions leading to early complications.
Diabetes mellitus (DM) is a major and increasing public health problem that may be underdiagnosed and undertreated among persons living with HIV (PLWH).
To describe the diagnosis, treatment and ...follow-up of DM among PLWH.
This study was performed inside a monocentric cohort of 1494 PLWH. DM was defined as having a FG ≥126 mg/dL twice or a HbA1c ≥6.5%, or a history of diabetes, or receiving antidiabetic treatment. The first visit mentioning a diagnosis of DM was considered as the baseline visit. Chi-Square or Fisher exact test were used to examine the association between categorical variables and DM, Wilcoxon or Student t-test were used for continuous variables.
156 PLWH with DM were included. Compared to non-diabetic participants, they were more likely to be native of Sub Saharan Africa (31.6% vs. 22.4%, p = 0.027) and older (54.6 vs. 49.9 years, p<0.001), to have a higher BMI (> 25 for 46.1% vs. 35.3%, p = 0.020) and a poorer control of HIV (HIV RNA<50 copies/mL: 80.1% vs. 89.5%, p<0.001). The diagnosis of DM was missed in 37.8% of PLWH, and 47.2% of PLWH treated for DM did not reach a HbA1c<7%. PLWH with DM were more frequently on antihypertensive and/or lipid-lowering medications: 94.2% had a LDL-cholesterol <70 mg/dL and 60.9% had a blood pressure <140/90 mmHg.
In a setting of HIV-control, HIV care providers should focus on metabolic issues. The management of DM and associated risk factors is mandatory to prevent cardiovascular disease in PLWH.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, ...and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated
knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. Metreleptin therapy had a beneficial effect in one patient. This translational study highlights the importance of epoxide regulation for adipocyte function and provides new insights into the physiological roles of EHs in humans.
Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads ...to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.
The seasonal evolution of O3 and its photochemical
production regime in a polluted region of eastern China between 2014 and 2017
has been investigated using observations. We used tropospheric ozone
...(O3), carbon monoxide (CO), and formaldehyde (HCHO, a marker of VOCs
(volatile organic compounds)) partial columns derived from high-resolution
Fourier transform spectrometry (FTS); tropospheric nitrogen dioxide
(NO2, a marker of NOx (nitrogen oxides)) partial
column deduced from the Ozone Monitoring Instrument (OMI); surface meteorological
data; and a back trajectory cluster analysis technique. A broad O3
maximum during both spring and summer (MAM/JJA) is observed; the day-to-day
variations in MAM/JJA are generally larger than those in autumn and winter
(SON/DJF). Tropospheric O3 columns in June are 1.55×1018 molecules cm−2 (56 DU (Dobson units)), and in December they are
1.05×1018 molecules cm−2 (39 DU). Tropospheric O3
columns in June were ∼50 % higher than those in December. Compared
with the SON/DJF season, the observed tropospheric O3 levels in MAM/JJA
are more influenced by the transport of air masses from densely populated and
industrialized areas, and the high O3 level and variability in
MAM/JJA is determined by the photochemical O3 production. The
tropospheric-column HCHO∕NO2 ratio is used as a proxy to
investigate the photochemical O3 production rate (PO3).
The results show that the PO3 is mainly nitrogen oxide (NOx) limited in MAM/JJA, while it is mainly VOC or mixed VOC–NOx limited in SON/DJF. Statistics show that
NOx-limited, mixed VOC–NOx-limited, and VOC-limited PO3 accounts for 60.1 %, 28.7 %, and 11 % of days,
respectively. Considering most of PO3 is NOx
limited or mixed VOC–NOx limited, reductions in
NOx would reduce O3 pollution in eastern China.
We present a consistent intercomparison of the mean age of air (AoA) according to five modern reanalyses: the European Centre for Medium-Range Weather Forecasts Interim Reanalysis (ERA-Interim), the ...Japanese Meteorological Agency's Japanese 55-year Reanalysis (JRA-55), the National Centers for Environmental Prediction Climate Forecast System Reanalysis (CFSR) and the National Aeronautics and Space Administration's Modern Era Retrospective analysis for Research and Applications version 1 (MERRA) and version 2 (MERRA-2). The modeling tool is a kinematic transport model driven only by the surface pressure and wind fields. It is validated for ERA-I through a comparison with the AoA computed by another transport model.
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