SUMMARY Numerous studies in humans link a nonsynonymous genetic polymorphism (I148M) in adiponutrin (ADPN) to various forms of fatty liver disease and liver cirrhosis. Despite its high clinical relevance, the molecular function of ADPN and the mechanism by which I148M variant affects hepatic metabolism are unclear. Here we show that ADPN promotes cellular lipid synthesis by converting lysophosphatidic acid (LPA) into phosphatidic acid. The ADPN-catalyzed LPA acyltransferase (LPAAT) reaction is specific for LPA and long-chain acyl-CoAs. Wild-type mice receiving a high-sucrose diet exhibit substantial upregulation of Adpn in the liver and a concomitant increase in LPAAT activity. In Adpn-deficient mice, this diet-induced increase in hepatic LPAAT activity is reduced. Notably, the I148M variant of human ADPN exhibits increased LPAAT activity leading to increased cellular lipid accumulation. This gain of function provides a plausible biochemical mechanism for the development of liver steatosis in subjects carrying the I148M variant.

Background: Micro-lipid droplets (mLDs) appear in adipocytes upon lipolytic stimulation. LDs may grow by spontaneous, homotypic fusion.Results: Scavenging of fatty acids prevents mLD formation. LDs grow by a slow transfer of lipids between LDs.Conclusion: mLDs form due to fatty acid overflow. LD growth is a controlled process.Significance: Novel mechanistic insights into LD remodeling are provided.

Albumin is the most abundant plasma protein. Critical illness is often associated with altered, predominately decreased, serum albumin levels. This hypoalbuminaemia is usually corrected by administration of exogenous albumin. This study aimed to track the concentration-dependent influence of albumin on blood coagulation in vitro. Whole blood (WB) samples from 25 volunteers were prepared to contain low (19.3 ± 7.7 g/L), physiological (45.2 ± 7.8 g/L), and high (67.5 ± 18.1 g/L) levels of albumin. Haemostatic profiling was performed using a platelet function analyzer (PFA) 200, impedance aggregometry, a Cone and Platelet analyzer (CPA), calibrated automated thrombogram, and thrombelastometry (TEM). Platelet aggregation-associated ATP release was assessed via HPLC analysis. In the low albumin group, when compared to the physiological albumin group, we found: i) shortened PFA 200-derived closure times indicating increased primary haemostasis; ii) increased impedance aggregometry-derived amplitudes, slopes, ATP release, as well as CPA-derived average size indicating improved platelet aggregation; iii) increased TEM-derived maximum clot firmness and alpha angles indicating enhanced clot formation. TEM measurements indicated impaired clot formation in the high albumin group compared with the physiological albumin group. Thus, albumin exerted significant anticoagulant action. Therefore, low albumin levels, often present in cancer or critically ill patients, might contribute to the frequently occurring venous thromboembolism.

Supplementary key words comparative gene identifi cation-58 • human lipolysis • regulation • insulin resistanceIn periods of nutrient scarcity or in response to increased energy demand, triglyceride (TG) stores are mobilized to provide free fatty acids (FFAs) as energy fuel. The mobilization of TGs is performed in three consecutive reactions, catalyzed by three lipases: adipose triglyceride lipase (ATGL) ( 1-3 ), hormone-sensitive lipase (HSL) ( 4 ), and monoglyceride lipase (MGL) ( 5 ). The crucial physiological role of ATGL (also annotated as patatin-like phospholipase domain containing 2, desnutrin, phospholipase A2 , and transport secretion protein 2.2) in lipolysis became evident by the phenotype of ATGL-defi cient (ATGL-ko) mice. ATGL-ko mice display increased whole-body fat mass, enlarged adipose fat depots, and TG accumulation in many tissues. Massive TG deposition in cardiomyocytes leads to cardiac insuffi ciency and premature death ( 6 ). In humans, the lack of ATGL activity, caused by mutations in the ATGL gene, is associated with a rare inherited disorder, annotated as neutral lipid storage disease with myopathy (NLSDM) ( 7 ). This disease is characterized by TG deposition in multiple tissues and cardiac myopathy.ATGL activity is strongly infl uenced by regulatory proteins. In 2006, Lass et al. identifi ed comparative gene identifi cation-58 (CGI-58, also known as ABHD5) as coactivator of Abstract The hydrolysis of triglycerides in adipocytes, termed lipolysis, provides free fatty acids as energy fuel. Murine lipolysis largely depends on the activity of adipose triglyceride lipase (ATGL), which is regulated by two proteins annotated as comparative gene identifi cation-58 (CGI-58) and G0/G1 switch gene-2 (G0S2). CGI-58 activates and G0S2 inhibits ATGL activity. In contrast to mice, the functional role of G0S2 in human adipocyte lipolysis is poorly characterized. Here we show that overexpression or silencing of G0S2 in human SGBS adipocytes decreases and increases lipolysis, respectively. Human G0S2 is upregulated during adipocyte differentiation and inhibits ATGL activity in a dose-dependent manner. Interestingly, C-terminally truncated ATGL mutants, which fail to localize to lipid droplets, translocate to the lipid droplet upon coexpression with G0S2, suggesting that G0S2 anchors ATGL to lipid droplets independent of ATGL's C-terminal lipid binding domain. Taken together, our results indicate that G0S2 also regulates human lipolysis by affecting enzyme activity and intracellular localization of ATGL. Increased lipolysis is known to contribute to the pathogenesis of insulin resistance, and G0S2 expression has been shown to be reduced in poorly controlled type 2 diabetic patients. Our data indicate that downregulation of G0S2 in adipose tissue could represent one of the underlying causes leading to increased lipolysis in the insulin-resistant state. -Schweiger, M., M. Paar, C. Eder, J. Brandis, E. Moser, G. Gorkiewicz, S. Grond, F. P. W. Radner, I. Cerk, I. Cornaciu, M. Oberer, S. Kersten, R. Zechner, ...

Energy metabolism, including alterations in energy intake and expenditure, is closely related to aging and longevity. Metabolomics studies have recently unraveled changes in metabolite composition in plasma and tissues during aging and have provided critical information to elucidate the molecular basis of the aging process. However, the metabolic changes in tissues responsible for food intake and lipid storage have remained unexplored. In this study, we aimed to investigate aging-related metabolic alterations in these tissues. To fill this gap, we employed NMR-based metabolomics in several tissues, including different parts of the intestine (duodenum, jejunum, ileum) and brown/white adipose tissues (BAT, WAT), of young (9–10 weeks) and old (96–104 weeks) wild-type (mixed genetic background of 129/J and C57BL/6) mice. We, further, included plasma and skeletal muscle of the same mice to verify previous results. Strikingly, we found that duodenum, jejunum, ileum, and WAT do not metabolically age. In contrast, plasma, skeletal muscle, and BAT show a strong metabolic aging phenotype. Overall, we provide first insights into the metabolic changes of tissues essential for nutrient uptake and lipid storage and have identified biomarkers for metabolites that could be further explored, to study the molecular mechanisms of aging.