Analysis of naturally occurring mutations in the human lipodystrophy protein seipin reveals multiple potential pathogenic mechanisms

Peer reviewedPublisher PD

Seipin oligomers can interact directly with AGPAT2 and lipin 1, physically scaffolding critical regulators of adipogenesis

This work was supported by a Merit Scholarship from the Islamic Development Bank (to M.M.U.T.), The Agency for Science, Technology and Research, Singapore (A*STAR) (M.F.M.S), the Medical Research Council (MRC) [NIRG GO800203 and Research Grant MR/L002620/1 (to J.J.R.), Program GrantG09000554 (to S.O.R)], The Wellcome Trust [078986/Z/06/Z (to S.O.R.)], the MRC Centre for Obesity and Related Metabolic Disorders (MRC-CORD) [GO600717] and the NIHR Comprehensive Biomedical Research Centre [CG50826].Peer reviewedPublisher PD

Deep subcutaneous application of poly-L-lactic acid as a filler for facial lipoatrophy in HIV-infected patients

Introduction: Facial lipoatrophy is a crucial problem of HIV-infected patients undergoing highly active antiretroviral therapy (HAART). Poly-L-lactic acid (PLA), provided as New-Fill(R)/Sculptra(TM), is known as one possible treatment option. In 2004 PLA was approved by the FDA as Sculptra(TM) for the treatment of lipoatrophy of the face in HIV-infected patients. While the first trials demonstrated relevant efficacy, this was to some extent linked to unwanted effects. As the depth of injection was considered relevant in this context, the application modalities of the preparation were changed. The preparation was to be injected more deeply into subcutaneous tissue, after increased dilution. Material and Methods: To test this approach we performed a pilot study following the new recommendations in 14 patients. Results: While the efficacy turned out to be about the same, tolerability was markedly improved. The increase in facial dermal thickness was particularly obvious in those patients who had suffered from lipoatrophy for a comparatively small period of time. Conclusion: With the new recommendations to dilute PLA powder and to inject it into the deeper subcutaneous tissue nodule formation is a minor problem. However, good treatment results can only be achieved if lipoatrophy is not too intense; treatment intervals should be about 2 - 3 weeks. Copyright (C) 2005 S. Karger AG, Basel

Myristic acid potentiates palmitic acid-induced lipotoxicity and steatohepatitis associated with lipodystrophy by sustaning de novo ceramide synthesis.

Palmitic acid (PA) induces hepatocyte apoptosis and fuels de novo ceramide synthesis in the endoplasmic reticulum (ER). Myristic acid (MA), a free fatty acid highly abundant in copra/palmist oils, is a predictor of nonalcoholic steatohepatitis (NASH) and stimulates ceramide synthesis. Here we investigated the synergism between MA and PA in ceramide synthesis, ER stress, lipotoxicity and NASH. Unlike PA, MA is not lipotoxic but potentiated PA-mediated lipoapoptosis, ER stress, caspase-3 activation and cytochrome c release in primary mouse hepatocytes (PMH). Moreover, MA kinetically sustained PA-induced total ceramide content by stimulating dehydroceramide desaturase and switched the ceramide profile from decreased to increased ceramide 14:0/ceramide16:0, without changing medium and long-chain ceramide species. PMH were more sensitive to equimolar ceramide14:0/ceramide16:0 exposure, which mimics the outcome of PA plus MA treatment on ceramide homeostasis, than to either ceramide alone. Treatment with myriocin to inhibit ceramide synthesis and tauroursodeoxycholic acid to prevent ER stress ameliorated PA plus MA induced apoptosis, similar to the protection afforded by the antioxidant BHA, the pan-caspase inhibitor z-VAD-Fmk and JNK inhibition. Moreover, ruthenium red protected PMH against PA and MA-induced cell death. Recapitulating in vitro findings, mice fed a diet enriched in PA plus MA exhibited lipodystrophy, hepatosplenomegaly, increased liver ceramide content and cholesterol levels, ER stress, liver damage, inflammation and fibrosis compared to mice fed diets enriched in PA or MA alone. The deleterious effects of PA plus MA-enriched diet were largely prevented by in vivo myriocin treatment. These findings indicate a causal link between ceramide synthesis and ER stress in lipotoxicity, and imply that the consumption of diets enriched in MA and PA can cause NASH associated with lipodystrophy

Berardinelli-Seip Syndrome

We have reported two cases of Berardinelli-syndrome in a family which is a rare autosomal recessive disorder of the adipose tissue, originally described by Berardinelli and Seip, has been reported in approximately 120 patients of various ethnic origins. Assuming that only 1 in 4 patients is reported.Patients present with acanthosis nigricans (dark velvety pigmentation of the skin) in the axilla, neck or groin, severe insulin resistance, high levels of serum insulin and serum triglycerides.The other clinical features consist of enlarged hands, feet and prominent mandible (acromegaloid features), increased sweating, umbilical hernia and lytic lesions (bone appear to be eaten-up on X-rays) in long bones of the upper and lower extremities (arms, forearm, hands, thigh, calf, legs and feet) such as humerus, femur, etc. Hepatomegaly from fatty liver is almost universal and may ultimately lead to cirrhosis. Splenomegaly is common. Nearly all patients have a prominent umbilicus or frank umbilical hernia. Females present with enlarged clitoris, increased body hair, absence of or irregular menstrual cycles, and polycystic ovaries (enlarged ovaries). Only a few affected women have had successful pregnancies, whereas affected men have normal fertilit

The metabolic syndrome- associated small G protein ARL15 plays a role in adipocyte differentiation and adiponectin secretion.

Common genetic variants at the ARL15 locus are associated with plasma adiponectin, insulin and HDL cholesterol concentrations, obesity, and coronary atherosclerosis. The ARL15 gene encodes a small GTP-binding protein whose function is currently unknown. In this study adipocyte-autonomous roles for ARL15 were investigated using conditional knockdown of Arl15 in murine 3T3-L1 (pre)adipocytes. Arl15 knockdown in differentiated adipocytes impaired adiponectin secretion but not adipsin secretion or insulin action, while in preadipocytes it impaired adipogenesis. In differentiated adipocytes GFP-tagged ARL15 localized predominantly to the Golgi with lower levels detected at the plasma membrane and intracellular vesicles, suggesting involvement in intracellular trafficking. Sequencing of ARL15 in 375 severely insulin resistant patients identified four rare heterozygous variants, including an early nonsense mutation in a proband with femorogluteal lipodystrophy and non classical congenital adrenal hyperplasia, and an essential splice site mutation in a proband with partial lipodystrophy and a history of childhood yolk sac tumour. No nonsense or essential splice site mutations were found in 2,479 controls, while five such variants were found in the ExAC database. These findings provide evidence that ARL15 plays a role in adipocyte differentiation and adiponectin secretion, and raise the possibility that human ARL15 haploinsufficiency predisposes to lipodystrophy

Does counseling increase sustained benefit of HAART among prison inmates after release to the community?

The lack of sustained effectiveness of HAART after release to the community of HIV-infected inmates treated in prison was well demonstrated by Springer et al. in a recent article. This disappointing result occurred even though all of the patients scheduled for release were referred for transitional case management services to a community-based organization and were provided with a 2-week supply of medications, a medical appointment with an HIV care provider, emergency housing and food, and assistance with other identified unmet needs

Immunovirological outcomes and resistance patterns at 4 years of antiretroviral therapy use in HIV-infected patients in Cambodia

Objectives  To report immunovirological outcomes and resistance patterns in adults treated with triple combination antiretroviral therapy (cART) for 4 years in an HIV programme of Phnom Penh, Cambodia. Methods  It is a longitudinal study and cross-sectional evaluation of adults receiving cART for 4 years. CD4 cell counts and HIV-1 RNA were quantified, and resistance patterns were determined. Drug-related toxicity was assessed by clinicians and through laboratory testing. Results  After 4 years of cART start, the cumulative probability of retention in care was 0.80 and survival among patients not lost to follow-up was 0.85. A total of 349 patients (98% of eligible) participated in the cross-sectional evaluation. Ninety per cent were receiving first-line therapy, 29% stavudine- and 58% zidovudine-containing regimens (compared with 94% and 3% at cART initiation). Ninety-three per cent of patients were clinically asymptomatic, and severe lipodystrophy and dyslipidemia were diagnosed in 7.2% and 4.0%, respectively. Good treatment adherence was reported by 83% of patients. Median CD4 T-cell count was 410 cells/μl [IQR 290-511], and 90% of patients had >200 cells/μl. Only 15 (4%) patients had detectable HIV viral load (eight had <200 CD4 cells/μl), five had thymidine analogue mutations, and nine were resistant to two drug classes. In an intention-to-treat analysis, 26.1% (95% CI 22.0-30.5) of patients had failed first-line therapy. Conclusions  In this Cambodian cohort of adults who started cART at an advanced stage of HIV disease, we observed good clinical and immunovirological outcomes and self-reported treatment adherence at 4 years of therapy