Can pancreatic steatosis affect exocrine functions of pancreas?

BACKGROUND/AIMS: Pancreatic steatosis (PS) is a generally used term to define accumulation of fat in the pancreas. In theory PS may be able to affect the exocrine function of pancreas. In this study we aimed to determine the effect of PS on exocrine pancreas function. MATERIALS AND METHODS: Forty-three patients with PS determined by 3 tesla magnetic resonance imaging (MRI) and 48 patients without PS were included in this study. Patients with PS were classified as group 1 and control patients were classified as group 2. Fecal elastase-1 levels were determined. Fecal elastase-1 levels <200 µg/g were defined as exocrine pancreatic insufficiency (EPI). Patients with PS were further grouped according to severity and anatomic distribution of steatosis based on findings of 3 tesla MRI. RESULTS: Fecal elastase-1 levels was significantly lower in group 1 compared to group 2 (319.76±45.7 vs 549.31±69.4, respectively, p=0.003). Proportion of patients with EPI was significantly higher in group 1 than group 2 (35.5% vs 12% p=0.042). There were no significant differences in terms of severity or the anatomic distribution of PS in patients with PS with EPI based on MRI (p=0.052, p=0.198, p=0.405) Conclusion: Current study demonstrates that PS can cause EPI.

Adipose triglyceride lipase acts on neutrophil lipid droplets to regulate substrate availability for lipid mediator synthesis.

In humans, mutations in ATGL lead to TG accumulation in LDs of most tissues and cells, including peripheral blood leukocytes. This pathologic condition is called Jordans' anomaly, in which functional consequences have not been investigated. In the present study, we tested the hypothesis that ATGL plays a role in leukocyte LD metabolism and immune cell function. Similar to humans with loss-of-function mutations in ATGL, we found that global and myeloid-specific Atgl(-/-) mice exhibit Jordans' anomaly with increased abundance of intracellular TG-rich LDs in neutrophil granulocytes. In a model of inflammatory peritonitis, lipid accumulation was also observed in monocytes and macrophages but not in eosinophils or lymphocytes. Neutrophils from Atgl(-/-) mice showed enhanced immune responses in vitro, which were more prominent in cells from global compared with myeloid-specific Atgl(-/-) mice. Mechanistically, ATGL(-/-) as well as pharmacological inhibition of ATGL led to an impaired release of lipid mediators from neutrophils. These findings demonstrate that the release of lipid mediators is dependent on the liberation of precursor molecules from the TG-rich pool of LDs by ATGL. Our data provide mechanistic insights into Jordans' anomaly in neutrophils and suggest that ATGL is a potent regulator of immune cell function and inflammatory diseases.

Trans-Golgi proteins participate in the control of lipid droplet and chylomicron formation.

LDs (lipid droplets) carrying TAG (triacylglycerol) and cholesteryl esters are emerging as dynamic cellular organelles that are generated in nearly every cell. They play a key role in lipid and membrane homoeostasis. Abnormal LD dynamics are associated with the pathophysiology of many metabolic diseases, such as obesity, diabetes, atherosclerosis, fatty liver and even cancer. Chylomicrons, stable droplets also consisting of TAG and cholesterol are generated in the intestinal epithelium to transport exogenous (dietary) lipids after meals from the small intestine to tissues for degradation. Defective chylomicron formation is responsible for inherited lipoprotein deficiencies, including abetalipoproteinaemia, hypobetalipoproteinaemia and chylomicron retention disease. These are disorders sharing characteristics such as fat malabsorption, low levels of circulating lipids and fat-soluble vitamins, failure to thrive in early childhood, ataxic neuropathy and visual impairment. Thus understanding the molecular mechanisms governing the dynamics of LDs and chylomicrons, namely, their biogenesis, growth, maintenance and degradation, will not only clarify their molecular role, but might also provide additional indications to treatment of metabolic diseases. In this review, we highlight the role of two small GTPases [ARFRP1 (ADP-ribosylation factor related protein 1) and ARL1 (ADP-ribosylation factor-like 1)] and their downstream targets acting on the trans-Golgi (Golgins and Rab proteins) on LD and chylomicron formation.

Precursor of ether phospholipids is synthesized by a flavoenzyme through covalent catalysis.

The precursor of the essential ether phospholipids is synthesized by a peroxisomal enzyme that uses a flavin cofactor to catalyze a reaction that does not alter the redox state of the substrates. The enzyme crystal structure reveals a V-shaped active site with a narrow constriction in front of the prosthetic group. Mutations causing inborn ether phospholipid deficiency, a very severe genetic disease, target residues that are part of the catalytic center. Biochemical analysis using substrate and flavin analogs, absorbance spectroscopy, mutagenesis, and mass spectrometry provide compelling evidence supporting an unusual mechanism of covalent catalysis. The flavin functions as a chemical trap that promotes exchange of an acyl with an alkyl group, generating the characteristic ether bond. Structural comparisons show that the covalent versus noncovalent mechanistic distinction in flavoenzyme catalysis and evolution relies on subtle factors rather than on gross modifications of the cofactor environment.

Multiple acyl-CoA-dehydrogenase deficiency (MADD)--a novel mutation of electron-transferring-flavoprotein dehydrogenase ETFDH.

This is the case of a 41 year old man, suffering general weakness and elevated liver enzymes, sensitive to a treatment with riboflavin and coenzyme Q(10). Tandem mass spectroscopy and molecular analysis reveal a multiple acyl-CoA-dehydrogenase deficiency (MADD) with two novel heterozygote missense mutations of the EFTDH gene.

Mutation of conserved cysteines in the Ly6 domain of GPIHBP1 in familial chylomicronemia.

We investigated a family from northern Sweden in which three of four siblings have congenital chylomicronemia. LPL activity and mass in pre- and postheparin plasma were low, and LPL release into plasma after heparin injection was delayed. LPL activity and mass in adipose tissue biopsies appeared normal. [(35)S]Methionine incorporation studies on adipose tissue showed that newly synthesized LPL was normal in size and normally glycosylated. Breast milk from the affected female subjects contained normal to elevated LPL mass and activity levels. The milk had a lower than normal milk lipid content, and the fatty acid composition was compatible with the milk lipids being derived from de novo lipogenesis, rather than from the plasma lipoproteins. Given the delayed release of LPL into the plasma after heparin, we suspected that the chylomicronemia might be caused by mutations in GPIHBP1. Indeed, all three affected siblings were compound heterozygotes for missense mutations involving highly conserved cysteines in the Ly6 domain of GPIHBP1 (C65S and C68G). The mutant GPIHBP1 proteins reached the surface of transfected Chinese hamster ovary cells but were defective in their ability to bind LPL (as judged by both cell-based and cell-free LPL binding assays). Thus, the conserved cysteines in the Ly6 domain are crucial for GPIHBP1 function.

Endolysosomal phospholipidosis and cytosolic lipid droplet storage and release in macrophages.

This review summarizes the current knowledge of endolysosomal and cytoplasmic lipid storage in macrophages induced by oxidized LDL (Ox-LDL), enzymatically degraded LDL (E-LDL) and other atherogenic lipoprotein modifications, and their relation to the adapter protein 3 (AP-3) dependent ABCA1 and ABCG1 cellular lipid efflux pathways. We compare endolysosomal lipid storage caused either through drug induced phospholipidosis, inheritable endolysosomal and cytosolic lipid storage disorders and Ox-LDL or E-LDL induced phagosomal uptake and cytosolic lipid droplet storage in macrophages. Ox-LDL is resistant to rapid endolysosomal hydrolysis and is trapped within the endolysosomal compartment generating lamellar bodies which resemble the characteristics of phospholipidosis. Various inherited lysosomal storage diseases including sphingolipidosis, glycosphingolipidosis and cholesterylester storage diseases also present a phospholipidosis phenotype. In contrast E-LDL resembling coreless unesterified cholesterol enriched LDL-particles, with a multilamellar, liposome-like structure, lead to rapid phagosomal degradation and cytosolic lipid droplet accumulation. As a consequence the uptake of E-LDL through type I and type II phagocytosis leads to increased lipid droplet formation and moderate upregulation of ABCA1 and ABCG1 while uptake of Ox-LDL leads to a rapid expansion of the lysosomal compartment and a pronounced upregulation of the ABCA1/ABCG1/AP-3 lipid efflux pathway.

Efecto del consumo de aguacate (persea amaricana mill): sobre el perfil lipídico en adultos con dislipidemia / Effect of consumption of avocado (persea americana mill): on the lipid profile in adults with dyslipidemia

Las dislipidemias son desórdenes metabólicos frecuentes, que se constituyen en un importante factor de riesgo de enfermedades, las cuales tienen como sustrato anatómico la aterosclerosis. El objetivo de este trabajo fue determinar el efecto del consumo de aguacate sobre los niveles plasmáticos de lípidos en individuos con dislipidemia. La muestra se conformó con 14 hombres: 6 (Grupo control) (GA) y 8 (Grupo experimental) (GB). Ambos grupos se evaluaron antropométricamente según los criterios de OMS y cumplieron una dieta (según los criterios de American Heart Association), más GA consumió 30 cc de aceite de maiz y el GB consumió 30 cc de grasa basados en aguacate en el almuerzo durante 30 días. Se midió Colesterol total, lipoproteínas de alta densidad (c-HDL), lipoproteínas de baja densidad (c-LDL), lipoproteínas de muy baja densidad (c-VLDL) y triacilglicéridos (TG) al inicio, 15 y 30 días. Para el análisis estadístico se aplicó T-student para datos no pareados (p < 0,005) con el programa SPSS 10 para Windows. El GA inició con CT= 232,6±37,1 mg/dL y finalizó con 206,7±34,8 mg/dL (p<0,000) (-13%). El GB inició con valores de CT= 222,9±15,2 mg/dL y finalizo en 206,3±17,2 mg/dL (p<0,000)(-9,2%). A los 30 días se encontró que TG disminuyeron 10,3% y c-HDL aumentó 6,3% en el grupo B; mientrasque c-LDL y c-VLDL tuvieron una disminución porcentual similar para ambos grupos. Se concluye que el consumo de aguacate en una comida mixta hipograsa puede ser beneficioso como estrategia terapéutica en la alimentación de adultos con esta patología.

Dyslipidemia are common metabolic disorder, which constitute a major risk factor for diseases which have the anatomic substrate atherosclerosis. The aim of this study was to determine the effect of the avocado on the plasma levels of lipids in subjects with dyslipidemia. The sample was formed with 14 men: 6 (control group) (GA) and 8 (experimental group) (GB). Anthropometrically Both groups were evaluated according to WHO criteria and met a diet (as determined by American Heart Association), consumed more GA 30 cc of corn oil and the GB consumed 30 cc of fat in the avocado-based lunch for 30 days. Measured total cholesterol, high-density lipoprotein (HDL-C), low density lipoprotein (LDL-c), very low density lipoproteins (VLDL-c) and Triacilglycerides (TG) at baseline, 15 and 30 days. For statistical analysis was applied to T-student data is not matched (p < 0.005) with the program SPSS 10 for Windows. The GA started with TC = 232.6 ± 37.1 mg/ dL and ended with 206.7 ± 34.8 mg/dL (p < 0.000) (-13%). GB began with the values of CT = 222.9 ± 15.2 mg/dL and finished at 206.3 ± 17.2 mg/dL (p < 0.000) (-9.2%). For the 30 days it was found that TG decreased 10.3% and increased HDL-c 6.3% in group B, while c-c-VLDL and LDL had a similar percentage decline for both groups. We conclude that consumption of avocado in a mixed meal hipograsa can be beneficial as a therapeutic strategy in the nutrition of adults with this condition.

Persistent growth failure in Prader-Willi syndrome associated with short-chain acyl-CoA dehydrogenase gene variant.

The authors report the rare association of Prader-Willi syndrome and short-chain acyl-CoA dehydrogenase gene variant. Prader-Willi syndrome, associated with paternal chromosome 15q11-q13 silencing, is characterized by neonatal/infantile hypotonia, growth failure, and neurodevelopmental delays in the first 1 to 2 years of life, typically followed by hyperphagia and obesity. Short-chain acyl-CoA dehydrogenase gene variant, with 625 G-to-A and 511 C-to-T changes, impairs C4-C6 fatty acid metabolism and variably causes neonatal/infantile hypotonia with developmental delays. The authors' patient continues to exhibit the classic severe growth failure of early infancy Prader-Willi syndrome at 40 months. Extensive laboratory investigations indicate that the short-chain acyl-CoA dehydrogenase gene variant is likely preventing or delaying the normal expression of the Prader-Willi syndrome phenotype.

Novel duplication mutation in the patatin domain of adipose triglyceride lipase (PNPLA2) in neutral lipid storage disease with severe myopathy.

Recently, mutations in PNPLA2 encoding adipose triglyceride lipase (ATGL) were reported to underlie a neutral lipid storage disease (NLSD) subgroup characterized by mild myopathy and the absence of ichthyosis. In the present study a novel homozygous PNPLA2 mutation c.475_478dupCTCC (p.Gln160ProfsX19) in the patatin domain, the ATGL active site, was detected in a woman with NLSD and severe myopathy. The present results suggest that a premature truncation mutation in the patatin domain causes NLSD with severe myopathy.