Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with its function cause lipodystrophy. PPARγ is a highly modular protein, and structural studies indicate that PPARγ domains engage in several intra- and inter-molecular interactions. How these interactions modulate PPARγ's ability to activate target genes in a cellular context is currently poorly understood. Here we take advantage of two previously uncharacterized lipodystrophy mutations, R212Q and E379K, that are predicted to interfere with the interaction of the hinge of PPARγ with DNA and with the interaction of PPARγ ligand binding domain (LBD) with the DNA-binding domain (DBD) of the retinoid X receptor, respectively. Using biochemical and genome-wide approaches we show that these mutations impair PPARγ function on an overlapping subset of target enhancers. The hinge region-DNA interaction appears mostly important for binding and remodelling of target enhancers in inaccessible chromatin, whereas the PPARγ-LBD:RXR-DBD interface stabilizes the PPARγ:RXR:DNA ternary complex. Our data demonstrate how in-depth analyses of lipodystrophy mutants can unravel molecular mechanisms of PPARγ function.

Background: The development of automated, smartphone application (app)-assisted home blood pressure monitoring (HBPM) allows for standardized measurement of blood pressure (BP) at home. The aim of this study was to evaluate the (diagnostic) agreement between app-assisted HBPM, automated office BP (OBP), and the reference standard 24-hour ambulatory BP monitoring (ABPM). Methods: In this open randomized 5-way cross-over study, patients diagnosed with hypertension were randomized to one of 10 clusters, each containing 5 BP measurement methods (ABPM, HBPM, attended OBP, unattended OBP, and unattended 30-minute BP) in different order. Results: In total, 113 patients were included. The average 24-hour ABPM was 126 +/- 11/73 +/- 8 mm Hg compared with 141 +/- 14/82 +/- 10 mm Hg with app-assisted HBPM, 134 +/- 13/80 +/- 9 mm Hg with unattended 30-minute BP, 137 +/- 16/81 +/- 11 mm Hg with attended OBP, and 135 +/- 15/81 +/- 10 mm Hg with unattended OBP monitoring. Diagnostic agreement between app-assisted HBPM and 24-hour ABPM for diagnosing sustained (OBP >140/90 mm Hg and ABPM >= 130/80 mm Hg or HBPM >= 135/85 mm Hg), white-coat (OBP >= 140/90 mm Hg and ABPM <130/80 mm Hg or HBPM <135/85 mm Hg), and masked hypertension (OBP <140/90 mm Hg and ABPM >= 130/80 mm Hg or HBPM >= 135/85 mm Hg) was fair-to-moderate (kappa statistics ranging from 0.34 to 0.40). App-assisted HBPM had high sensitivities (78%-91%) and negative predictive values (90%-97%) for diagnosing sustained and masked hypertension. Conclusions: This study showed a considerable (diagnostic) disagreement between app-assisted HBPM and ABPM. App-assisted HBPM had high sensitivity in the diagnosis of sustained and masked hypertension and may therefore be used as complementary to, but not a replacement of, ABPM.

Editorial for “Assessment of Imaging Modalities Against Liver Biopsy in Nonalcoholic Fatty Liver Disease: The Amsterdam NAFLD-NASH Cohort” Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide with a recent study suggesting a prevalence of 38% in the United States. While the disease is reaching epidemic levels, there is still no recognized pharmacological treatment and there is a massive drive to address this unmet clinical need. Histologically assessed fibrosis and resolution of nonalcoholic steatohepatitis (NASH) remain the only surrogate endpoints accepted by the regulators for studies in patients without cirrhosis. Furthermore, the presence of NASH with significant fibrosis or with cirrhosis is a requirement for inclusion in clinical trials. The limitations of liver biopsy are therefore impeding drug development programs due to high screen failure rates, patient reluctance to participate, and higher numbers of patients needed to achieve sufficient statistical power. Noninvasive biomarkers of liver fibrosis and NASH that could be used instead of liver biopsy for the purposes of clinical trials could therefore revolutionize the field. Magnetic resonance techniques, such as magnetic resonance elastography, proton density fat fraction (PDFF) mapping, and T1 mapping, are attractive as they offer noninvasive assessment and potentially whole-liver coverage eliminating sampling variability. There are now extensive data to support some of these techniques as noninvasive measures of fibrosis, but noninvasive assessment of NASH remains largely unfulfilled. Liver stiffness measurements (LSM) are now routinely carried out using ultrasound-based vibration-controlled transient elastography (VCTE). Newer VCTE machines can provide controlled attenuation parameter (CAP) readings of liver steatosis in addition to LSM. CAP measurements are approximating the attenuation coefficient of ultrasound in the liver, and as this coefficient is different based on the tissue composition, it is expected to have a dependence on the amount of fat present in the hepatocytes. However, it is still unclear to what extent CAP measurements alone can be used to assess steatosis grades. While correlation between CAP and steatosis grade has been reported, some also show a lack of significant difference between CAP measurements in patients with steatosis grades 2 and 3, or even between grades 1 and 2. This variable performance in diagnosing steatosis grades coupled with cut-offs that are often very close to each other with overlapping confidence intervals means that CAP cannot yet be used as an easy, point-of-care method of determining severity of steatosis. In this issue of JMRI, Troelstra et al present the initial results from the Amsterdam NAFLD-NASH cohort (ANCHOR) study. The investigators aim to improve the noninvasive diagnosis and follow-up of individuals with various grades and stages of NAFLD. Results in the first 37 subjects describe the use of multiparametric magnetic resonance imaging (MRI) to predict NAFL vs. NASH, the degree of steatosis, the degree of lobular inflammation and hepatocyte ballooning, and the degree of fibrosis. Overall, the results presented indicate that multiparametric MRI is a promising noninvasive method for the accurate assessment of steatosis and fibrosis severity, with the potential to distinguish between simple hepatic steatosis and NASH. Troelstra et al also found that CAP measurements did not correlate with histological steatosis grade while MRS and two measures of PDFF did correlate significantly with histological steatosis. The study is well conducted, and these results add to the growing body of studies that develop combinations of imaging biomarkers and, potentially, plasma biomarkers to predict the presence of NASH, the inflammation activity grade, and the fibrosis stage in subjects with NAFLD. A major limitation is the limited number of subjects included and the lack of spread in the subjects’ SAF scores with a concentration of subjects with steatosis grade 2, inflammation activity grade A1-2, and fibrosis stage F2. However, recruitment in ANCHOR is ongoing and future results when more subjects have been recruited are eagerly anticipated.

Despite limited evidence about the efficacy and safety of anticoagulation in patients post bariatric surgery, both vitamin K antagonists (VKA) and direct-acting oral anticoagulants (DOACs) are commonly prescribed. To evaluate plasma anti-Xa levels of DOACs in morbidly obese (MO) patients before and after a Roux-en-Y gastric bypass (RYGB) procedure. Retrospective, cross-sectional, and longitudinal study of anti-Xa activity of apixaban or rivaroxaban in MO patients (N = 41). Preoperative analysis of plasma anti-Xa levels were within the normal range in patients using apixaban (n = 29; body mass index [BMI] 44.5 ± 5.1 kg/m2) as well as those using rivaroxaban (n = 12; BMI 42.6 ± 5.9 kg/m2). Postoperative anti-Xa levels of apixaban were all within the therapeutic range, whereas anti-Xa levels of rivaroxaban were subtherapeutic in nine out of 14 (64%) patients. Perioperative longitudinal follow-up in patients using apixaban (n = 18) showed no significant change in anti-Xa levels after RYGB. Plasma anti-Xa levels of apixaban in MO patients remained within the therapeutic range up to a body weight of 144 kg. In patients using rivaroxaban, no statistically significant relation between anti-Xa levels and bodyweight was found. After RYGB, plasma anti-Xa levels of apixaban were unaffected, whereas plasma anti-Xa levels of rivaroxaban tended to become subtherapeutic.

Background Patients with primary aldosteronism (PA) experience more cardiovascular events compared to patients with essential hypertension (EHT), independent from blood pressure levels. In animals, mineralocorticoid receptor antagonists limit ischaemia-reperfusion (IR) injury by increasing extracellular adenosine formation and adenosine receptor stimulation. Adenosine is an endogenous compound with profound cardiovascular protective effects. Firstly, we hypothesized that patients with PA have lower circulating adenosine levels which might contribute to the observed increased cardiovascular risk. Secondly, we hypothesized that by this mechanism, patients with PA are more susceptible to IR compared to patients with EHT. Design In our prospective study in 20 patients with PA and 20 patients with EHT, circulating adenosine was measured using a pharmacological blocker solution that halts adenosine metabolism after blood drawing. Brachial artery flow-mediated dilation (FMD) before and after forearm IR was used as a well-established method to study IR injury. Results Patients with PA had a 33% lower adenosine level compared to patients with EHT (15.3 [13.3-20.4] vs 22.7 [19.4-36.8] nmol/L, respectively, P .01). The reduction in FMD after IR, however, did not differ between patients with PA and patients with EHT (-1.0 +/- 2.9% vs -1.6 +/- 1.6%, respectively, P = .52). Conclusions As adenosine receptor stimulation induces various powerful protective cardiovascular effects, its lower concentration in patients with PA might be an important novel mechanism that contributes to their increased cardiovascular risk. We suggest that modulation of the adenosine metabolism is an exciting novel pharmacological opportunity to limit cardiovascular risk in patients with PA that needs further exploration.

Abstract Context Primary aldosteronism (PA) confers an increased risk of cardiovascular disease (CVD), independent of blood pressure. Animal models have shown that aldosterone accelerates atherosclerosis through proinflammatory changes in innate immune cells; human data are scarce. Objective The objective of this article is to explore whether patients with PA have increased arterial wall inflammation, systemic inflammation, and reprogramming of monocytes. Design A cross-sectional cohort study compared vascular inflammation on 2’-deoxy-2’-(18F)fluoro-D-glucose; (18F-FDG) positron emission tomography–computed tomography, systemic inflammation, and monocyte phenotypes and transcriptome between PA patients and controls. Setting This study took place at Radboudumc and Rijnstate Hospital, the Netherlands. Patients Fifteen patients with PA and 15 age-, sex-, and blood pressure-matched controls with essential hypertension (EHT) participated. Main Outcome Measures and Results PA patients displayed a higher arterial 18F-FDG uptake in the descending and abdominal aorta (P < .01, P < .05) and carotid and iliac arteries (both P < .01). In addition, bone marrow uptake was higher in PA patients (P < .05). Although PA patients had a higher monocyte-to-lymphocyte ratio (P < .05), systemic inflammatory markers, cytokine production capacity, and transcriptome of circulating monocytes did not differ. Monocyte-derived macrophages from PA patients expressed more TNFA; monocyte-derived macrophages of healthy donors cultured in PA serum displayed increased interleukin-6 and tumor necrosis factor-α production. Conclusions Because increased arterial wall inflammation is associated with accelerated atherogenesis and unstable plaques, this might importantly contribute to the increased CVD risk in PA patients. We did not observe inflammatory reprogramming of circulating monocytes. However, subtle inflammatory changes are present in the peripheral blood cell composition and monocyte transcriptome of PA patients, and in their monocyte-derived macrophages. Most likely, arterial inflammation in PA requires interaction between various cell types.

Objective: The nuclear receptor PPAR gamma is the master regulator of adipocyte differentiation, distribution, and function. In addition, PPAR gamma induces terminal differentiation of several epithelial cell lineages, including colon epithelia. Loss-of-function mutations in PPARG result in familial partial lipodystrophy subtype 3 (FPDL3), a rare condition characterized by aberrant adipose tissue distribution and severe metabolic complications, including diabetes. Mutations in PPARG have also been reported in sporadic colorectal cancers, but the significance of these mutations is unclear. Studying these natural PPARG mutations provides valuable insights into structure-function relationships in the PPAR gamma protein. We functionally characterized a novel FPLD3-associated PPAR gamma L451P mutation in helix 9 of the ligand binding domain (LBD). Interestingly, substitution of the adjacent amino acid K450 was previously reported in a human colon carcinoma cell line. Methods: We performed a detailed side-by-side functional comparison of these two PPAR gamma mutants. Results: PPAR gamma L451P shows multiple intermolecular defects, including impaired cofactor binding and reduced RXR alpha heterodimerisation and subsequent DNA binding, but not in DBD-LBD interdomain communication. The K450Q mutant displays none of these functional defects. Other colon cancer-associated PPAR gamma mutants displayed diverse phenotypes, ranging from complete loss of activity to wildtype activity. Conclusions: Amino acid changes in helix 9 can differently affect LBD integrity and function. In addition, FPLD3-associated PPAR gamma mutations consistently cause intra- and/or intermolecular defects; colon cancer-associated PPAR gamma mutations on the other hand may play a role in colon cancer onset and progression, but this is not due to their effects on the most well-studied functional characteristics of PPAR gamma. (C) 2018 The Authors. Published by Elsevier GmbH.

Genetic lipodystrophies are a group of rare syndromes associated with major metabolic complications - including severe insulin resistance, type 2 diabetes mellitus, and hypertriglyceridemia - which are classified according to the distribution of adipose tissue. Lipodystrophies can be present at birth or develop during life and can range from local to partial and general. With at least 18 different genes implicated so far, definite diagnosis can be challenging due to clinical and genetic heterogeneity. In an adult female patient with clinical and metabolic features of partial lipodystrophy we identified via whole genome sequencing (WGS) a single complex AGPAT2 allele [V67M;V167A], functionally equivalent to heterozygosity. AGPAT2 encodes for an acyltransferase implicated in the biosynthesis of triacylglycerol and glycerophospholipids. So far homozygous and compound heterozygous mutations in AGPAT2 have only been associated with generalized lipodystrophy. A SNP risk score analysis indicated that the index patient is not predisposed to lipodystrophy based on her genetic background. The partial phenotype in our patient is therefore more likely associated to the genetic variants in AGPAT2. To test whether the resulting double-mutant AGPAT2 protein is functional we analyzed its in vitro enzymatic activity via mass spectrometry. The resulting AGPAT2 double mutant is enzymatically inactive. Our data support the view that the current classification of lipodystrophies as strictly local, partial or generalized may have to be re-evaluated and viewed more as a continuum, both in terms of clinical presentation and underlying genetic causes. Better molecular understanding of lipodystrophies may lead to new therapies to treat adipose tissue dysfunction in common and rare diseases.

We investigated the postprandial changes in plasma levels of adipocytokines in overweight patients with metabolic syndrome after an oral fat load. After an oral fat load and during a prolonged fast, blood was drawn at 0, 2, 3, 4 and 8 h for measurement of adiponectin, adipsin, cathepsin S, chemerin, hepatic growth factor, interferon-γ-inducible protein-10, leptin, macrophage chemoattractant protein-1, macrophage migration inhibitory factor, nerve growth factor, retinol binding protein-4, resistin, serum amyloid A1, tissue inhibitor of metalloproteinase-1 and thrombopoietin using a microbead-based Luminex assay. Area under the curves (AUC) were calculated and compared. Plasma adiponectin levels were higher after an oral fat load compared to fasting at t = 2 h (950 ± 513 vs. −1,881 ± 713 ng/ml) while the plasma levels for adipsin (−9 ± 5 vs. 16 ± 5 ng/ml), chemerin (−122 ± 35 vs. 13 ± 21 ng/ml), SAA-1 (−391 ± 213 vs. 522 ± 173 ng/ml) and TPO (−335 ± 144 vs. 622 ± 216 ng/ml) were lower after an oral fat load compared to fasting. The baseline corrected AUC for IP-10 was higher after fat load compared to fasting (median −116 pg h/ml; IQR −270 to 10 vs. −21 pg h/ml; IQR −136 to 418 ( p = 0.047). In conclusion, in overweight male subjects with the metabolic syndrome, an oral fat load is accompanied with a modest anti-inflammatory response of adipose tissue-derived adipocytokines.

BackgroundWe investigated whether plasma ferritin levels through the pro-inflammatory effects of free iron are associated with adipose tissue dysfunction in a relevant population of patients with manifest vascular disease who would potentially benefit the most from further aetiological insights.Materials and methodsIn a cohort of 355 patients with vascular diseases, the association between plasma ferritin and adiponectin levels was quantified using linear regression analysis. Interleukin-6 and adiponectin levels were measured in medium from pre-adipocytes and adipocytes after incubation with increasing concentrations of Fe(III)-citrate and after co-incubation with iron chelators or radical scavengers.ResultsIncreasing ferritin plasma concentrations were not related to plasma adiponectin levels in patients without ( -013; 95% CI -030 to 004) or with the metabolic syndrome ( -004; 95% CI -017 to 010). Similar results were found in patients who developed a new cardiovascular event in the follow-up period. In vitro, incubation with increasing concentrations of Fe(III)-citrate-induced inflammation in pre-adipocyte cultures as witnessed by increased IL-6 secretion at 30m Fe(III)-citrate vs. control (50098pg/mL vs. 194 +/- 31pg/mL, P=003). Co-incubation of pre-adipocytes with iron chelators or radical scavengers prevented this inflammatory response. Incubation of adipocytes with 30m Fe(III)-citrate did not influence adiponectin secretion compared with control.ConclusionsIn patients with vascular disease, there is no association between plasma ferritin and adiponectin levels. In vitro, free iron induces an inflammatory response in pre-adipocytes, but not in adipocytes. This response was blocked by co-incubation with iron chelators or radical scavengers. Adiponectin secretion by adipocytes was not influenced by free iron.

Background Plasma triglyceride (TG) levels are known to confer an increased risk of vascular disease in healthy populations, but data in high-risk patients are scarce. In this study we evaluated the risk on recurrent vascular events conferred by increased plasma TG levels in patients with various clinical manifestations of vascular disease. Methods Prospective cohort study of 5731 patients with clinically manifest vascular disease. Results First new vascular events (myocardial infarction, ischemic stroke, vascular death) occurred in 782 subjects during a median follow-up of 4.9years (interquartile range 2.5–8.1years). Patients in the highest plasma TG quintile (>2.24mmol/L) had a higher risk for recurrent vascular events (HR 1.45; 95%CI 1.13–1.86) compared with the lowest plasma TG quintile (<0.97mmol/L) after adjustments for age, gender, body mass index, smoking, lipid-lowering medication and low-density lipoprotein-cholesterol. The increased risk associated with increasing plasma TG levels was irrespective of the presence of type 2 diabetes (T2DM), but only present in patients without the metabolic syndrome. Furthermore, the increased risk was particularly present in patients with coronary artery disease (CAD) (HR 1.45; 95%CI 1.02–2.08) and was not modified by other lipid levels (p-value for interaction >0.05). Plasma TG still contributed to vascular risk when other lipid levels were at target level. Conclusions Higher plasma TG levels are associated with increased risk for recurrent vascular events, in particular in CAD patients. This increased risk is independent of the presence of T2DM and the use of lipid-lowering medication and is not modified by other lipid levels.

Background Increased production of chemokines by adipose tissue and defective adipose tissue oxygenation as a result of obesity may induce leucocyte infiltration and subsequent systemic inflammation. Objectives 1-To determine the relation between the amount of visceral and subcutaneous adipose tissue and the chemokine interferon--inducible protein 10 (IP-10) and angiogenic factor hepatocyte growth factor (HGF). 2-To determine the relation between the metabolic syndrome and IP-10 as well as HGF. Methods Patients originated from the Secondary Manifestations of ARTerial disease (SMART) cohort. In this study, a cohort of 1251 patients with manifest vascular disease was included. Subcutaneous and visceral adipose tissue thickness (SAT and VAT respectively) were measured ultrasonographically. IP-10 and HGF concentrations were measured with Luminex multiplex immuno assay in addition to fasting metabolic parameters. Linear regression analyses with adjustments for age, gender, smoking, estimated glomerular filtration rate, type 2 diabetes mellitus and medication use were applied to quantify the relations between adiposity or metabolic syndrome and IP-10 and HGF concentrations. Results VAT was significantly associated with (log)IP-10 and (log)HGF, reflected by significant higher -values in VAT quartile 4 compared with VAT quartile 1 (reference): 0.155 (95%CI:0.0730.237) for IP-10 and 0.147 (95%CI:0.0760.218) for HGF. Per standard deviation increase in VAT, (log)IP-10 levels increased with 0.057pg/mL (95%CI:0.0270.087) and (log)HGF increased with 0.051pg/mL (95%CI:0.0250.077). Effect estimates were not affected by including body mass index(BMI) in the model. In contrast, SAT was not associated with IP-10 and HGF. Furthermore, the presence of the metabolic syndrome was associated with IP-10 and HGF. Conclusions Visceral adipose tissue but not subcutaneous adipose tissue is significantly associated with circulating levels of IP-10 and HGF, irrespective of BMI.

Familial partial lipodystrophy type 3 (FPLD) is an autosomal dominant disease characterized by aberrant adipose distribution and metabolic disturbances, including insulin resistance and dyslipidemia.

Obesity and its metabolic complications are important risk factors for cardiovascular disease. Obesity is associated with adipose tissue (AT) inflammation, initiated by adipocyte hypertrophy and ultimately resulting in low-grade systemic inflammation. Complex intercellular communication between adipocytes and AT-resident immune cells underlie AT inflammation.

The alarming and still increasing prevalence of obesity and associated cardiovascular risk raises much concern. The increase in cardiovascular risk depends to a significant extent on the changes in lipid profiles as observed in obesity These changes are decreased high-density lipoprotein cholesterol and increased triglyceride levels. Much effort has already been expended into the elucidation of the mechanisms behind these obesity-associated lipid changes. Insulin resistance certainly plays a central role and, in addition, both hormonal and neurologic pathways have recently been found to play an important role. This article focuses on the mechanisms involved in the development of the proatherogenic lipid changes associated with obesity.

The inverse correlation between HDL-C and atherosclerotic vascular disease is well established and lately research has focused on HDL as a potential target in the treatment of vascular disease. Traditionally, reverse cholesterol transport is considered to be the most important mechanism by which HDL protects against atherosclerosis. However, recent findings indicate that the role of HDL as an antiatherogenic particle is much more complex and research has focused on additional protective mechanisms, such as anti-inflammatory and antioxidative characteristics. However, these additional properties are still a matter of debate and currently no standardized, reproducible, high-throughput assays that can quantify those characteristics of HDL are available. Here we discuss the current knowledge on reverse cholesterol transport and the enzymes involved in HDL synthesis and remodeling. The interactions of the HDL particle with other cells that might play a crucial role in the additional protective mechanisms of HDL are also highlighted.

CONTEXT Familial partial lipodystrophy (FPLD) results from coding sequence mutations either in LMNA, encoding nuclear lamin A/C, or in PPARG, encoding peroxisome proliferator-activated receptor-gamma (PPARgamma). The LMNA form is called FPLD2 (MIM 151660) and the PPARG form is called FPLD3 (MIM 604367). OBJECTIVE Our objective was to investigate whether the clinical phenotype of this proband is due to mutation(s) in PPARgamma. DESIGN This is a case report. Patient and Setting: A 31-yr-old female with the clinical phenotype of FPLD3, i.e. lipodystrophy and early childhood diabetes with extreme insulin resistance and hypertriglyceridemia leading to recurrent pancreatitis, was assessed at an academic medical center. RESULTS The proband was heterozygous for a novel C-->T mutation in the PPARG gene that led to the substitution of arginine 194 in PPARgamma2 isoform, a conserved residue located in the zinc finger structure involved in DNA binding, by tryptophan (R194W). The mutation was absent from the genomes of 100 healthy Caucasians. In vitro analysis of the mutated protein showed that R194W (and R166W in PPARgamma1 isoform) could not bind to DNA and had no transcriptional activity. Furthermore, R194W had no dominant-negative activity. CONCLUSIONS The R194W mutation in PPARG disrupts its DNA binding activity and through haploinsufficiency leads to clinical manifestation of FPLD3 and the associated metabolic disturbances.

Lipodystrophies represent a heterogeneous group of diseases characterized by an abnormal subcutaneous fat distribution, the extent of which can vary from localized, to partial, to generalized lipoatrophy. Whereas partial and generalized lipodystrophies are each associated with metabolic abnormalities, the localized form is not. These metabolic changes include insulin resistance with type 2 diabetes, acanthosis nigricans, dyslipidaemia predominantly consisting of hypertriglyceridaemia (associated with the onset of pancreatitis) and depressed HDL cholesterol, liver steatosis and hypertension. Affected women are often hirsute and this can be associated with the presence of polycystic ovarian syndrome (PCOS). Most of these clinical features are present to some extent in patients with the common metabolic syndrome. As the prevalence of metabolic syndrome far outweighs that of lipodystrophy, the diagnosis of this rare disorder may often be overlooked with the affected patient diagnosed as merely being ‘yet’ another case of metabolic syndrome. In this article, we draw attention to the importance of recognizing patients with lipodystrophy who present with metabolic abnormalities, as both the diagnostic as well as the therapeutic approach of these patients differ profoundly from patients with the metabolic syndrome.

We report here the molecular cloning of a novel member of the triglyceride lipase family, a 2.4-kb cDNA encoding human lipase H (LIPH) and the mouse ortholog (Liph). The human LIPH cDNA encodes a 451-amino-acid protein with a lipase domain. Mouse Liph shows 85% amino acid identity and 75% nucleotide identity to human LIPH. Human LIPH exhibits 47% identity with phosphatidylserine-specific phospholipase A1 (PS-PLA1) and 46% identity with endothelial lipase (LIPG) and lipoprotein lipase (LPL). LIPH is localized on human chromosome 3q27-q28. Northern blot analysis revealed specific expression of LIPH mRNA in intestine, lung, and pancreas. Lipase H protein was also detected in human intestine. Lipase H is a secreted protein with an apparent molecular weight of 63 kDa. Although several lipid substrates were tested, the lipid substrate of LIPG was not identified. Like the other members of this gene family, LIPH may be involved in lipid and energy metabolism.