Hormone-sensitive lipase (HSL) was initially characterized as the hormonally regulated neutral lipase activity responsible for the breakdown of triacylglycerols into fatty acids in adipose tissue. This review aims at providing up-to-date information on structural properties, regulation of expression, activity and function as well as therapeutic potential. The lipase is expressed as different isoforms produced from tissue-specific alternative promoters. All isoforms are composed of an N-terminal domain and a C-terminal catalytic domain within which a regulatory domain containing the phosphorylation sites is embedded. Some isoforms possess additional N-terminal regions. The catalytic domain shares similarities with bacteria, fungus and vascular plant proteins but not with other mammalian lipases. HSL singularity is provided by regulatory and N-terminal domains sharing no homology with other proteins. HSL has a broad substrate specificity compared to other neutral lipases. It hydrolyzes acylglycerols, cholesteryl and retinyl esters among other substrates. A novel role of HSL, independent of its enzymatic function, has recently been described in adipocytes. Clinical studies revealed dysregulations of HSL expression and activity in disorders, such as lipodystrophy, obesity, type 2 diabetes and cancer-associated cachexia. Development of specific inhibitors positions HSL as a pharmacological target for the treatment of metabolic complications.

• MeSH
• diabetes mellitus 2. typu * MeSH
• lipolýza MeSH
• sterolesterasa * genetika   metabolismus   MeSH
• tuková tkáň metabolismus   MeSH
• tukové buňky metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Branched esters of palmitic acid and hydroxy stearic acid are antiinflammatory and antidiabetic lipokines that belong to a family of fatty acid (FA) esters of hydroxy fatty acids (HFAs) called FAHFAs. FAHFAs themselves belong to oligomeric FA esters, known as estolides. Glycerol-bound FAHFAs in triacylglycerols (TAGs), named TAG estolides, serve as metabolite reservoir of FAHFAs mobilized by lipases upon demand. Here, we characterized the involvement of two major metabolic lipases, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in TAG estolide and FAHFA degradation. We synthesized a library of 20 TAG estolide isomers with FAHFAs varying in branching position, chain length, saturation grade, and position on the glycerol backbone and developed an in silico mass spectra library of all predicted catabolic intermediates. We found that ATGL alone or coactivated by comparative gene identification-58 efficiently liberated FAHFAs from TAG estolides with a preference for more compact substrates where the estolide branching point is located near the glycerol ester bond. ATGL was further involved in transesterification and remodeling reactions leading to the formation of TAG estolides with alternative acyl compositions. HSL represented a much more potent estolide bond hydrolase for both TAG estolides and free FAHFAs. FAHFA and TAG estolide accumulation in white adipose tissue of mice lacking HSL argued for a functional role of HSL in estolide catabolism in vivo. Our data show that ATGL and HSL participate in the metabolism of estolides and TAG estolides in distinct manners and are likely to affect the lipokine function of FAHFAs.

• MeSH
• bílá tuková tkáň metabolismus   MeSH
• estery chemie   MeSH
• HEK293 buňky MeSH
• kyselina palmitová metabolismus   MeSH
• kyseliny stearové metabolismus   MeSH
• lidé MeSH
• lipasa metabolismus   MeSH
• lipolýza fyziologie   MeSH
• mastné kyseliny metabolismus   MeSH
• metabolismus fyziologie   MeSH
• myši knockoutované MeSH
• myši MeSH
• sterolesterasa metabolismus   MeSH
• triglyceridy metabolismus   MeSH
• tuková tkáň metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND AND AIMS: Lysosomal acid lipase deficiency is characterized by hepatomegaly and dyslipidaemia, which can lead to cirrhosis and premature atherosclerosis. Sebelipase alfa is an approved recombinant human lysosomal acid lipase. In an open-label extension study of adults with lysosomal acid lipase deficiency (LAL-CL04), sebelipase alfa treatment for 1 year reduced serum transaminase levels and liver fat content and improved serum lipid levels. METHODS: Final data from LAL-CL04 are reported herein for patients who received sebelipase alfa infusions (1.0 or 3.0 mg/kg every other week) for up to 5 years. RESULTS: Of 8 patients enrolled, 7 received sebelipase alfa for 224-260 weeks; 1 was lost to follow-up. Median baseline levels of alanine aminotransferase and aspartate aminotransferase (81.5 and 50.0 U/L, respectively) were decreased through the end-of-study visit (54.0 and 34.0 U/L). Median low-density lipoprotein cholesterol decreased from 113 to 78 mg/dL, total cholesterol decreased from 171 to 132 mg/dL, and high-density lipoprotein cholesterol increased from 37 to 42 mg/dL. Most treatment-emergent adverse events were nonserious (99%), mild/moderate (98%) and unrelated to sebelipase alfa (87%); no patient discontinued as a result of treatment-emergent adverse events. One patient had 2 serious treatment-emergent adverse events (cholecystitis and cholelithiasis; assessed as unlikely related to sebelipase alfa). Two patients had 20 nonserious infusion-associated reactions in weeks 6-38; all were manageable. One patient tested positive for antidrug antibodies (single occurrence). CONCLUSIONS: Sebelipase alfa was well tolerated and improved serum transaminase and lipid levels for up to 5 years in adults with lysosomal acid lipase deficiency. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov record NCT01488097.

• MeSH
• alanintransaminasa MeSH
• dospělí MeSH
• lidé MeSH
• sterolesterasa * MeSH
• Wolmanova nemoc * farmakoterapie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• práce podpořená grantem MeSH

• MeSH
• akademie a ústavy MeSH
• dyslipidemie * farmakoterapie   MeSH
• kardiovaskulární nemoci mortalita   prevence a kontrola   MeSH
• klinická studie jako téma MeSH
• kongresy jako téma MeSH
• lidé MeSH
• monoklonální protilátky ekonomika   terapeutické užití   MeSH
• odběr vzorku krve MeSH
• omezení příjmu potravy krev   MeSH
• PCSK9 inhibitory MeSH
• proproteinkonvertasa subtilisin/kexin typu 9 MeSH
• riziko MeSH
• schvalování léčiv ekonomika   MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• sterolesterasa nedostatek   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• zprávy MeSH

In-vitro investigation of the effects of hypoxia is limited by physical laws of gas diffusion and cellular O2 consumption, making prolonged exposures to stable O2 concentrations impossible. Using a gas-permeable cultureware, chronic effects of mild and severe hypoxia on triglyceride accumulation, lipid droplet size distribution, spontaneous lipolysis and gene expression of adipocyte-specific markers were assessed. 3T3-L1 cells were differentiated under 20%, 4% or 1% O2 using a gas-permeable cultureware. Triglyceride accumulation, expression of genes characteristic for advanced adipocyte differentiation and involvement of key lipogenesis enzymes were assessed after exposures. Lipogenesis increased by 375% under mild hypoxia, but dropped by 43% in severe hypoxia. Mild, but not severe, hypoxia increased formation of large lipid droplets 6.4 fold and strongly induced gene expression of adipocyte-specific markers. Spontaneous lipolysis increased by 488% in mild, but only by 135% in severe hypoxia. Inhibition of ATP-dependent citrate lyase suppressed hypoxia-induced lipogenesis by 81% and 85%. Activation of HIF inhibited lipogenesis by 59%. Mild, but not severe, hypoxia stimulates lipolysis and promotes adipocyte differentiation, probably through excess of acetyl-CoA originating from tricarboxylic acid cycle independently of HIF activation.

• MeSH
• acetylkoenzym A metabolismus   MeSH
• adipogeneze účinky léků   genetika   MeSH
• ATP-citrát-(pro-S)-lyasa genetika   metabolismus   MeSH
• buněčná diferenciace účinky léků   MeSH
• buňky 3T3-L1 MeSH
• citrátový cyklus účinky léků   genetika   MeSH
• diacylglycerol-O-acyltransferasa genetika   metabolismus   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa genetika   metabolismus   MeSH
• hypoxie buňky MeSH
• kyslík farmakologie   MeSH
• lipidová tělíska chemie   účinky léků   MeSH
• lipogeneze účinky léků   genetika   MeSH
• lipolýza účinky léků   genetika   MeSH
• myši MeSH
• perilipin 1 genetika   metabolismus   MeSH
• proteiny vázající mastné kyseliny genetika   metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• signální transdukce MeSH
• sterolesterasa genetika   metabolismus   MeSH
• triglyceridy metabolismus   MeSH
• tukové buňky cytologie   účinky léků   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Cachectic rheumatoid arthritis, the less frequent form of the disease, is associated with loss of fat mass and often more severe course of the disease. Its experimental model represents rat adjuvant arthritis (AA) characterized by edema, lack of appetite, sharp body weight and fat loss. As individual fat depots display functional differences, here we studied lipolytic activity and sensitivity to lipolytic stimuli of nodeless epididymal fat (eWAT) and perinodal mesenteric fat (mWAT) depots at the peak of AA. We also examined changes in catecholamine and cytokine levels involved in lipolysis in plasma and/or isolated adipocytes from both WATs to identify the contribution of local, adipocyte-based processes and/or systemic events to adiposity loss in cachectic rheumatoid arthritis. AA was induced to male Lewis rats by complete Freund's adjuvant. Groups of ad libitum-fed and pair-fed controls were used to distinguish the effects of food restriction from inflammation-induced cachexia. Adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL) and its phosphorylated form (pHSL) were analyzed by western blot. CRP and catecholamine levels in plasma or adipocyte lysates were determined using ELISA kits. Cytokine-induced neutrophil chemoattractant-1 (CINC-1/CXCL1), monocyte chemoattractant protein-1 (MCP-1/CCL2), IL-1β, IL-6, IL-10 and leptin in adipocyte lysate were analyzed by quantitative protein microarray. Plasma glycerol and FFA were measured spectrophotometrically. AA rats developed severe cachexia, with lower adiposity in mWAT compared to normal and pair-fed controls, whereas in eWAT the adiposity was similarly reduced in AA and pair-fed groups. ATGL levels in both WATs were not affected by AA or pair feeding. AA upregulated levels of HSL, pHSL and pHSL/HSL ratio in mWAT, whereas none of these parameters has changed in eWAT of AA rats or in either WATs of pair-fed rats. In AA rats plasma glycerol was elevated, whereas FFA concentration was reduced. Plasma norepinephrine and epinephrine were increased in AA compared with both groups of controls. In eWAT adipocytes, AA but not pair feeding, upregulated norepinephrine levels. In mWAT adipocytes, AA rats showed higher epinephrine levels than pair-fed controls. Leptin levels in both WATs were depleted in AA animals in accordance with body weight loss. None of the measured cytokines in eWAT and mWAT was enhanced. Our results demonstrate augmented lipolytic activity in mWAT and not eWAT during cachectic arthritis. The adipocyte-derived cytokines do not seem to contribute to activated lipolysis. We first demonstrated enhanced presence of norepinephrine in perinodal adipocytes that may contribute to the regulation of local lipolytic activity by auto/paracrine fashion and thus provide independent fuel supply to activated lymph nodes.

• MeSH
• adrenalin biosyntéza   MeSH
• artritida experimentální imunologie   metabolismus   MeSH
• biologické markery MeSH
• C-reaktivní protein MeSH
• epididymis metabolismus   MeSH
• humorální imunita MeSH
• krysa rodu rattus MeSH
• lipolýza MeSH
• mezenterium metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• sterolesterasa metabolismus   MeSH
• tukové buňky metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: The aim of this study was to characterize key clinical manifestations of lysosomal acid lipase deficiency (LAL D) in children and adults. METHODS: Investigators reviewed medical records of LAL D patients ages ≥5 years, extracted historical data, and obtained prospective laboratory and imaging data on living patients to develop a longitudinal dataset. RESULTS: A total of 49 patients were enrolled; 48 had confirmed LAL D. Mean age at first disease-related abnormality was 9.0 years (range 0-42); mean age at diagnosis was 15.2 years (range 1-46). Twenty-nine (60%) were male patients, and 27 (56%) were <20 years of age at the time of consent/assent. Serum transaminases were elevated in most patients with 458 of 499 (92%) of alanine aminotransferase values and 265 of 448 (59%) of aspartate aminotransferase values above the upper limit of normal. Most patients had elevated low-density lipoprotein (64% patients) and total cholesterol (63%) at baseline despite most being on lipid-lowering therapies, and 44% had high-density lipoprotein levels below the lower limit of normal. More than half of the patients with liver biopsies (n = 31, mean age 13 years) had documented evidence of steatosis (87%) and/or fibrosis (52%). Imaging assessments revealed that the median liver volume was ∼1.15 multiples of normal (MN) and median spleen volume was ∼2.2 MN. Six (13%) patients had undergone a liver transplant (ages 9-43.5 years). CONCLUSION: This study provides the largest longitudinal case review of patients with LAL D and confirms that LAL D is predominantly a pediatric disease causing early and progressive hepatic dysfunction associated with dyslipidemia that often leads to liver failure and transplantation.

• MeSH
• alanintransaminasa krev   MeSH
• aspartátaminotransferasy krev   MeSH
• cholesterol krev   MeSH
• dítě MeSH
• dospělí MeSH
• jaterní cirhóza etiologie   MeSH
• játra * metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipasa nedostatek   MeSH
• longitudinální studie MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoc ze střádání esterů cholesterolu * krev   patologie   MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• slezina patologie   MeSH
• sterolesterasa nedostatek   MeSH
• transplantace jater MeSH
• Wolmanova nemoc * krev   patologie   MeSH
• ztučnělá játra krev   etiologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Lysosomal acid lipase is an essential lipid-metabolizing enzyme that breaks down endocytosed lipid particles and regulates lipid metabolism. We conducted a phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, an underappreciated cause of cirrhosis and severe dyslipidemia. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study involving 66 patients, we evaluated the safety and effectiveness of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg per kilogram of body weight every other week); the placebo-controlled phase of the study was 20 weeks long and was followed by open-label treatment for all patients. The primary end point was normalization of the alanine aminotransferase level. Secondary end points included additional disease-related efficacy assessments, safety, and side-effect profile. RESULTS: Substantial disease burden at baseline included a very high level of low-density lipoprotein cholesterol (≥190 mg per deciliter) in 38 of 66 patients (58%) and cirrhosis in 10 of 32 patients (31%) who underwent biopsy. A total of 65 of the 66 patients who underwent randomization completed the double-blind portion of the trial and continued with open-label treatment. At 20 weeks, the alanine aminotransferase level was normal in 11 of 36 patients (31%) in the sebelipase alfa group and in 2 of 30 (7%) in the placebo group (P=0.03), with mean changes from baseline of -58 U per liter versus -7 U per liter (P<0.001). With respect to prespecified key secondary efficacy end points, we observed improvements in lipid levels and reduction in hepatic fat content (P<0.001 for all comparisons, except P=0.04 for triglycerides). The number of patients with adverse events was similar in the two groups; most events were mild and were considered by the investigator to be unrelated to treatment. CONCLUSIONS: Sebelipase alfa therapy resulted in a reduction in multiple disease-related hepatic and lipid abnormalities in children and adults with lysosomal acid lipase deficiency. (Funded by Synageva BioPharma and others; ARISE ClinicalTrials.gov number, NCT01757184.).

• MeSH
• alanintransaminasa krev   MeSH
• biopsie MeSH
• dítě MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• dyslipidemie farmakoterapie   genetika   MeSH
• HDL-cholesterol krev   MeSH
• játra účinky léků   patologie   MeSH
• LDL-cholesterol krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• senioři MeSH
• sterolesterasa škodlivé účinky   farmakologie   terapeutické užití   MeSH
• Wolmanova nemoc krev   farmakoterapie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND & AIMS: Lysosomal acid lipase deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. METHODS: Sebelipase alfa (1mg/kg or 3mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. RESULTS: 216 infusions were administered to eight adult subjects through week 52 during LAL-CL04. At week 52, mean alanine aminotransferase and aspartate aminotransferase levels were normal with mean change from baseline of -58% and -40%. Mean changes for low-density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were -60%, -39%, -36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of a hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. CONCLUSIONS: Long-term dosing with sebelipase alfa in lysosomal acid lipase-deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in the hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184).

• MeSH
• alanintransaminasa krev   MeSH
• aspartátaminotransferasy krev   MeSH
• dospělí MeSH
• játra patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipidy krev   MeSH
• mladý dospělý MeSH
• rekombinantní proteiny aplikace a dávkování   škodlivé účinky   MeSH
• rozvrh dávkování léků MeSH
• sterolesterasa aplikace a dávkování   škodlivé účinky   nedostatek   MeSH
• Wolmanova nemoc krev   farmakoterapie   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

We present data supporting the hypothesis that the lysosomal-autophagy pathway is involved in the degradation of intracellular triacylglycerols in the liver. In primary hepatocytes cultivated in the absence of exogenous fatty acids (FFA), both inhibition of autophagy flux (asparagine) or lysosomal activity (chloroquine) decreased secretion of VLDL (very low density lipoproteins) and formation of FFA oxidative products while the stimulation of autophagy by rapamycine increased some of these parameters. Effect of rapamycine was completely abolished by inactivation of lysosomes. Similarly, when autophagic activity was influenced by cultivating the hepatocytes in "starving" (amino-acid poor medium) or "fed" (serum-supplemented medium) conditions, VLDL secretion and FFA oxidation mirrored the changes in autophagy being higher in starvation and lower in fed state. Autophagy inhibition as well as lysosomal inactivation depressed FFA and DAG (diacylglycerol) formation in liver slices in vitro. In vivo, intensity of lysosomal lipid degradation depends on the formation of autophagolysosomes, i.e. structures bringing the substrate for degradation and lysosomal enzymes into contact. We demonstrated that lysosomal lipase (LAL) activity in liver autophagolysosomal fraction was up-regulated in fasting and down-regulated in fed state together with the increased translocation of LAL and LAMP2 proteins from lysosomal pool to this fraction. Changes in autophagy intensity (LC3-II/LC3-I ratio) followed a similar pattern.

• MeSH
• asparagin farmakologie   MeSH
• autofagie účinky léků   MeSH
• chlorochin farmakologie   MeSH
• diglyceridy metabolismus   MeSH
• hepatocyty metabolismus   patologie   účinky léků   MeSH
• játra metabolismus   patologie   účinky léků   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• kyseliny mastné neesterifikované metabolismus   MeSH
• lipolýza MeSH
• lipoproteiny VLDL metabolismus   MeSH
• lyzozomy metabolismus   patologie   účinky léků   MeSH
• membránový protein 2 asociovaný s lyzozomy metabolismus   MeSH
• oxidace-redukce MeSH
• potkani Wistar MeSH
• proteiny asociované s mikrotubuly metabolismus   MeSH
• sirolimus farmakologie   MeSH
• sterolesterasa metabolismus   MeSH
• triglyceridy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH