Liver Dystrophy Research Articles

Influence of milk thistle pressed parts on rats liver histology

Milk thistle (Silybum marianum) is one of the best known and very often used herbs with positive effect on liver. The aim of this article was to study influence of addition of milk thistle pressed parts in feed ration on liver histology and weight increase of laboratory rats. The experiment was tested by 15 pieces of laboratory rats divided into 3 groups (A, B, C). The rats in first group (A) hade feed ration with addition of 10% milk thistle pressed parts, second group (B) hade feed ration with 20% and control group (C) hade feed ration without addition of milk thistle pressed parts. The silymarin content of pressed milk thistle seed was 26.2 mg/g. The aim of this article is to study influence of addition of milk thistle pressed parts in feed ration on liver histology and weight increase of laboratory rats. The hypothesis is that the feeding addition - milk thistle seed pressed parts has positive effect on weight performance and liver histology. Does the feeding addition have any effect on these health indicators? Does feeding of milk thistle seed pressed parts have any sense? In results, the groups with addition of milk thistle had significant bigger average gain increases than the control group. Histological results vary considerably among groups of rats. All rats in the control group had dystrophic liver with sinusoidal congestion. In most rats of the group A, the dystrophy was minimal without congestion. On the other hand, most of rats of the group B had liver dystrophy caused by large droplets steatosis with congestion. All rats in control group C were found to have significant dystrophy caused by steatosis. The results indicate rats receiving the addition of milk thistle pressed parts in their feed had a lower incidence of liver steatosis due to the hepatoprotective effects of silymarin.

Деякі макроскопічні зміни у внутрішніх органах поросят-сисунів за колібактеріозу

In recent years the country has significantly decreased not only the number of pigs, but also the production of the pork. In many households, it has become unprofitable. It is established that one of the reasons of decrease in manufacture of pork is too high the waste of young (35–40% of born piglets). In this critical situation there are many factors, but one of these are communicable diseases, particularly Colibacteriosis. Colibacteriosis is an acute infectious disease of young animals, from the literature it is known that sick piglets in the first days (5–7 days after birth, and less commonly 7–14 days). The percentage loss of piglets infected with Colibacteriosis in the age of 1–14 days is 35–40% and more. The main causes of their illness consider infected the surrounding objects, colostrum, dairy utensils, air, hands and clothing of attendants, as well as contact with rats and home mice. Also, one of the main causes of morbidity piglets is a violation of the zoo technical and veterinary-sanitary rules of the maintenance, feeding and care of ewes, newborn animals and young animals during the period of weaning from the ewes. This disease is prevalent in many countries, including it is widespread in pig farms of Ukraine. In the available domestic and foreign literature adequately describes the diagnosis and treatment of Colibacteriosis in piglets, but macroscopic changes are described incompletely.The aim of this work was to examine in more detail the macroscopic changes in internal organs of piglets that died from Colibacteriosis. To achieve this goal were the following objectives: to conduct a postmortem autopsy of piglets infected with Colibacteriosis, and to study macroscopic changes in internal organs of animals with this disease and describe macroscopic changes in internal organs that were not previously described. The research was carried out during 2016–2017 years on the basis of one of the pig farms of industrial type and of the Department of pathological anatomy, National University of life and environmental Sciences of Ukraine. The material for the study served as the corpses of 10 piglets that died from Colibacteriosis. Postmortem autopsy of piglets, carried out in the dorsal position by the method of partial evisceration at the Department of pathological anatomy of the University. When conducting autopsy piglets that died from Colibacteriosis were established following changes in the internal organs of animals: serous inflammation of the small intestine, serous-hemorrhagic lymphadenitis, in the spleen were recorded hyperplasia of lymphoid nodules and hypertrophy, granular dystrophy of liver and heart, and venous congestion and pulmonary edema.

Гістологічні зміни в котів за хламідіозу

The article presents the results of the study of histological changes in organs and tissues of cats for chlamydial infection. The histopathological examination of the postmortem cases of cats (n = 8) of different breeds between the ages of 3 to 6 years old, who lives with the laboratory methods have been diagnosed and identified the pathogen Chlamydia felis. According to historical data from sick animals were recorded various nature and degree of conjunctivitis and pronounced signs of a lesion of the respiratory tract (rhinitis, bronchitis, pneumonia). The made histological sections were stained with hematoxylin and eosin according to routine standard methods. The general histological structure and microstructural changes in histological preparations were studied under a light microscope. The histopathological examination were confirmed and specified the pathoanatomical diagnoses, established after autopsy of dead animals. It is shown that the most pronounced damage and characteristic changes all dead cats fixed contact in lung tissues and regional lymph nodes (mediastinal and bronchial), and in the spleen. The morphological criteria of chlamydial infection in the studied dead animals at the microscopic level were as follows:1) interstitial pneumonia; 2) pulmonary fibrosis; 3) fibrinous-purulent pleuropneumonia; 4) hyperplasia and serous lymphadenitis of the mediastinal and bronchial lymph nodes; 5) hyperplasia of lymphoid nodules of the spleen; 6) passive venous congestion of the liver and kidneys; 7) fatty and granular liver dystrophy. The results of our study, the pathomorphological diagnosis of chlamydial infection in most of the cats that died was based on changes characteristic of interstitial pneumonia followed pneumosclerosis or fibrinous-purulent pleuropneumonia, with deep affection of the bronchial epithelium. Consequently, the features of chlamydial infection are such that the clinical picture does not always correspond to the severity of morphological manifestations and complications of infection. Weak clinical manifestations can be combined with significant destructive, degenerative and necrotic changes in organs and tissues.

Профілактика хвороб печінки у курей яєчного напрямку продуктивності

The article gives brief statistics of state poultry industry in Ukraine, its importance in the market of the country and problematics. The most common pathologies of non-contagious etiology in poultry associated with impaired metabolism are examined in the article. The data on age features of metabolism, level of metabolic processes and critical physiological and technological periods in laying hen sis shown. The greatest load takes over the liver, which is directly or indirectly involved in all metabolic and functional changes of hepatocytes cause a breach in the systems of organs and in organism as a whole. The analysis of scientific literature and numerous studies in recent years shows that the disease of the liver (hepatosis or dystrophy of hepatocytes, hepatitis and cirrhosis) are very common among poultry and are composed from 5.0 to 50.8% of all non-communicable diseases. A feature of these diseases is hidden (subclinical) course, which complicates their timely diagnosis and effective prevention. One direction solution to the problem is to normalize metabolic processes in the body and morpho-functional state of the liver is to use hepatoprotectors. It is established that the group of these medications in recent years, acquired widespread adoption due to the intensive rearing of poultry and for protection their organism against unfavorable external and internal environment. Hepatoprotectors, improving metabolism in the liver, provide intensive growth, development and high productivity of poultry. The selection studies of physiological period of laying hens for using hepatoprotectors in the prevention of liver diseases is required, in particular hepatosis for conducting clinical examination of how the system measures to prevent metabolic diseases of poultry. It is necessary to improve methods of early diagnosis the dysfunction of the liver and use effective methods of correction of metabolic processes.

ПАТОЛОГОАНАТОМИЧЕСКИЕ ИЗМЕНЕНИЯ ПРИ АССОЦИАТИВНОМ ТЕЧЕНИИ ЭЙМЕРИОЗА И САЛЬМОНЕЛЛЕЗА НУТРИЙ

The aim of the research is justification of causal relationship patterns of Salmonella and Eimeria, and their role in the pathology of the disease. The authors analyzed the incidence of salmonellosis nutria and eimeriosis depending on the way of the content. 82 the corpses of nutria was conducted post-mortem autopsy and bacteriological examination. For bacteriological examination were selected the heart, lungs, liver with gallbladder, spleen, kidney, brain, mesenteric lymph nodes, bone from fresh corpses. It is established that in conditions of the same economy under the cellular content of the disease were not recorded, and if outdoor, how and when the content of the deep litter, and on the concrete floor had equally widespread. In the study of pathologic material derived from carcasses of dead nutria, have the following distribution of serovars: S. dublin – 22.8%, S. typhimurium – 40.3%, S. choleraesuis – is 36.9%. For bacteriological tests crops held at IBA, with marked diffuse haze. On Endo agar grew transparent slightly bluish or pinkish colonies 2-4 mm in diameter, on the environment Ploskirev – turbid, more dense, Levin – transparent with slight purple tint on the Wilson-Blair – black with a metallic luster. The culture obtained were studied by optical microscopy, detecting single spaced, do not form spores and capsules with a length of 1-4 µm, with a diameter of 0.5-0.8 μm, sticks. For associative flow of Salmonella and Eimeria nutria characteristic of chronic catarrhal gastritis, acute catarrhal-gemorragicescom-necrotic enterocolitis, congestive redness of the serous membranes of the small and large intestine, mesentery, granular and adipose dystrophy of liver, granular dystrophy of kidneys, myocardium, gemorragicescom-necrotic splenic, acute serous lymphadenitis, congestive hyperemia and edema of the lungs, brain and other organs, hemorrhagic diathesis.

Behavioral features of mice fed with a cholesterol-enriched diet:Deficient novelty exploration and unaltered aggressive behavior

ObjectivesPrevious studies involving mice have demonstrated that a cholesterol-enriched diet evokes liver steatosis, dystrophy, inflammation, and aspects of nonalcoholic fatty liver disease (NAFLD)...

The Relationship of Obesity to the Character of Nutrition

The aim of the investigation was to study pathogenesis of abdominal obesity on the model of experimental fatty dystrophy in rats; to assess the state of lipid and protein metabolism and to elucidate morpho-biochemical interrelations between pathogenesis of fatty liver dystrophy and character of nutrition. Male Wistar rats (n = 42, weight 210 g) were object of the research. Three groups of animals were formed: rats of group 1 (control group, n = 15) received standard vivarium diet; rats of group 2 (n = 15) received hypercaloric fatty diet with allyl alcohol; rats of group 3 (with alloxan diabetes, n = 12) also received hypercaloric fatty diet with allyl alcohol. Rats were maintained on these diets for 90 days and were controlled every 30 days. Dynamics of body mass of animals after 90 days of feeding was: group 1--from 200 ± 10 to 230 ± 10, group 2--from 200 ± 10 to 385 ± 5, group 3--from 200 ± 10 to 400 ± 10 g. Dynamic development of obesity and liver dystrophy is caused by disturbances of lipid and protein metabolism at the background of imbalance of alimentary fat and metabolic changes. Lipid disorganization is caused by the deficiency of the hepatrophic factors.

Tenesmus in a calf with hepatic encephalopathy

A 7.6-week-old male Simmental calf was presented because of vehement tenesmus. Clinical neurological examination revealed sensomotoric dysfunction. Clinical pathology indicated a severe liver dystrophy and cholestasis. Laboratory parameters of cerebrospinal...

A controlled trial on the effect of feeding dietary chestnut extract and glycerol monolaurate on liver function in newborn calves

SummaryBeginning in the fall of 2010, an increasing and alarming number of cases of calves suffering from liver dystrophy were reported in the south of Germany. An epidemiological investigation was carried out by the authors between November 2010 and July 2011, leading to the implication of a commercial dietary supplement as the potential cause for this outbreak. The components of this product were first tested in a cell culture model and two of them (dietary chestnut extract and glycerol monolaurate) showed a cytotoxic effect. The objective of this study was therefore to evaluate the effect of supplemental feeding of both components alone or in combination on liver function in newborn calves on a commercial dairy farm. Ten calves were enrolled in each of the three treatment groups and the control group (group O) following a blocked design. Treatment consisted of supplementation with chestnut extract at 0.02% of birth body mass (BM) (group C), supplementation with glycerol monolaurate at 0.006% of BM (group G) or a combined treatment (group CG) for five consecutive days. The effect of treatments on liver function was evaluated clinically and by measurement of glutamate dehydrogenase (GLDH) and aspartate aminotransferase (AST) activities as well as the determination of the concentrations of glucose, L‐lactate and total bilirubin in serum. There was a significant increase in GLDH and AST activities and a significant decrease in glucose concentration in treatment groups C and CG compared with the control group (p ≤ 0.035), whereas no difference was shown for group G. Survival was significantly decreased in groups C (p = 0.029) and CG (p = 0.001) compared with both group G and the control group. These results suggest that dietary chestnut extract in an amount of 0.02% of BM alone or in combination has a toxic effect on liver function in newborn calves.

Histomorphological structure of the liver in roach (Rutilus rutilus) and pike (Esox lucius) from lakes with different levels of anthropogenic impact

Using histological techniques, changes in histomorphological characteristics of the liver were revealed in two fish species from lakes with different levels of anthropogenic impact. The most significant changes in the liver of roach from Kostomukshskoe Lake (used as a tailing dump of the Kostomuksha Mining and Ore-processing Plant) included initial stages of parenchymal protein dystrophy and, to a lesser extent, fatty dystrophy; in pike, fatty liver dystrophy prevailed. Compared to roach, pike proved to be more sensitive to ecological conditions in Kostomukshskoe lake, including increased water mineralization. In both fish species from Koivas Lake (20 km from the pollution source), only the initial stages of local dystrophic changes could be detected. The fish from clean Kamennoe Lake (located in a protected area) had no pathological changes in the liver.

Lebensbedrohliche, maternale Leberaffektionen in der späten Schwangerschaft und im Wochenbett – eine Fallserie mit Überblick über Pathogenese und differenzialdiagnostische Abgrenzung

A severe hepatopathy constitutes a serious threat during pregnancy and poses considerable challenges to the treating physicians. A broad spectrum of pregnancy-dependent or independent diseases like HELLP-syndrome, liver infection or acute fatty liver of pregnancy (AFLP) is characterized by these affections of the liver. In this study, we present a series of 3 cases with life-threatening hepatopathies and discuss the current state of the literature. A special focus is placed on pathogenesis and differential diagnosis. Pathological, radiological and gynaecological/surgical procedures were performed according to the current German guidelines. Laboratory tests were conducted in the clinics' routine diagnostics section. The existing literature was reviewed via the US National Library of Medicine database “PubMed.gov”. The first patient had been afflicted by a fulminant HELLP syndrome causing delivery after 32 weeks of pregnancy. Consecutively, she suffered a sub-total liver infarction followed by a severe coagulopathy and septic peritonitis. The second patient was diagnosed with HELLP syndrome at 36 weeks of pregnancy. The initially mild syndrome exacerbated after delivery leading to haemorrhagic shock and acute renal failure. In the third case, a woman with asymptomatic hepatitis B delivered in the 36th week of pregnancy. Post partum, her pre-existing condition worsened fulminantly resulting in sub-acute liver dystrophy and massive coagulopathy. Whenever a hepatopathy occurs during pregnancy, several divergent diagnoses with severe implications and different aetiopathologies have to be considered. Diagnostic and therapeutic strategies have to be weighed quickly to enable a fast, interdisciplinary cooperation in order to prevent fatal outcomes.

Relation between serum enzymes and liver histopathology in mink with hepatitis

The dystrophy of the mink liver is widely distributed in mink farms of Latvia. However, clinical diagnostics of the liver dystrophy is quite difficult. The hypothesis of this study was to clarify the indicators of ALT (alanine aminotransferase) and ALP (alkaline phosphatase) as the criteria in the early diagnostics of the mink liver injury. The goal of this study was to determine the potential correlation between the expressed functional indicators and the histopathology of the liver. Blood samples were obtained from ten minks, seropositive against the Aleutian disease. Liver injury was assessed histologically. Through application of the biotin-streptavidine immunohistochemical method, the presence of the hepatocyte growth factor, as well as the basal membrane components was established in the mink liver tissue, but liver apoptosis was determined by TUNEL. For the assessment of cytokines, a semi-quantitative counting method was used. The results showed the apoptosis of the hepatocytes in the whole area of the liver parenchyma. The correlation between the apoptosis and the expression of inflammation cells in the mink liver was non-existent. Constitutive release of cytokines (Hsp 70 and HGF) was detected in the liver hepatocytes centrilobular or around the periportal area. We established that have the mean correlation existed between the moderate steatosis and the weak HGF expression. Hsp 70 expression in hepatocytes was higher when moderate and numerous apoptotic cells were seen. The ALT level of the experimental mink in 40% cases was incresed above the standard. Interconnection between the degree of gravity of steatosis and the increasing of ALP and ALT levels was not found. We concluded that the simultaneous presence of the infiltration of inflammatory cells and the moderate expression of HGF detect the still maintained regeneration ability of liver despite the persisting inflammation. The increased activity of liver enzymes (ALT and ALP) does not directly depend on the damaged mink liver disorders and can be suggested only as a common indicator for the liver dysfunctioning of mink with the Aleutian disease.

Fluorescence spectroscopy measures yeast PAH1-encoded phosphatidate phosphatase interaction with liposome membranes

Phosphatidate (PA) phosphatase, the enzyme that catalyzes the penultimate step in triacylglycerol synthesis, is a cytosolic enzyme that must associate with the membrane where its substrate PA resides. Fluorescence spectroscopy was used to measure the interaction of yeast PAH1-encoded PA phosphatase with model liposome membranes. PA phosphatase contains five tryptophan residues and exhibited inherit fluorescence that increased upon interaction with phosphatidylcholine liposomes. The interaction was enhanced by inclusion of other phospholipids and especially the substrate PA. Interaction was dependent on both the concentration of phosphatidylcholine-PA liposomes as well as the surface concentration of PA in liposomes. Mg(2+) ions, which were required for catalysis, did not affect PA phosphatase interaction with phosphatidylcholine-PA liposomes. PA phosphatase was a substrate for protein kinase A, protein kinase C, and casein kinase II, and these phosphorylations decreased PA phosphatase interaction with phosphatidylcholine-PA liposome membranes.

Nuclear Envelope Phosphatase 1-Regulatory Subunit 1 (Formerly TMEM188) Is the Metazoan Spo7p Ortholog and Functions in the Lipin Activation Pathway

Lipin-1 catalyzes the formation of diacylglycerol from phosphatidic acid. Lipin-1 mutations cause lipodystrophy in mice and acute myopathy in humans. It is heavily phosphorylated, and the yeast ortholog Pah1p becomes membrane-associated and active upon dephosphorylation by the Nem1p-Spo7p membrane complex. A mammalian ortholog of Nem1p is the C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1, formerly "dullard"), but its Spo7p-like partner is unknown, and the need for its existence is debated. Here, we identify the metazoan ortholog of Spo7p, TMEM188, renamed nuclear envelope phosphatase 1-regulatory subunit 1 (NEP1-R1). CTDNEP1 and NEP1-R1 together complement a nem1Δspo7Δ strain to block endoplasmic reticulum proliferation and restore triacylglycerol levels and lipid droplet number. The two human orthologs are in a complex in cells, and the amount of CTDNEP1 is increased in the presence of NEP1-R1. In the Caenorhabditis elegans embryo, expression of nematode CTDNEP1 and NEP1-R1, as well as lipin-1, is required for normal nuclear membrane breakdown after zygote formation. The expression pattern of NEP1-R1 and CTDNEP1 in human and mouse tissues closely mirrors that of lipin-1. CTDNEP1 can dephosphorylate lipins-1a, -1b, and -2 in human cells only in the presence of NEP1-R1. The nuclear fraction of lipin-1b is increased when CTDNEP1 and NEP1-R1 are co-expressed. Therefore, NEP1-R1 is functionally conserved from yeast to humans and functions in the lipin activation pathway.

Relationship of glucose and oleate metabolism to cardiac function in lipin-1 deficient (fld) mice

Lipin-1 is the major phosphatidate phosphatase (PAP) in the heart and a transcriptional coactivator that regulates fatty acid (FA) oxidation in the liver. As the control of FA metabolism is essential for maintaining cardiac function, we investigated whether lipin-1 deficiency affects cardiac metabolism and performance. Cardiac PAP activity in lipin-1 deficient [fatty liver dystrophy (fld)] mice was decreased by >80% compared with controls. Surprisingly, oleate oxidation and incorporation in triacylglycerol (TG), as well as glucose oxidation, were not significantly different in perfused working fld hearts. Despite this, [³H]oleate accumulation in phosphatidate and phosphatidylinositol was increased in fld hearts, reflecting the decreased PAP activity. Phosphatidate accumulation was linked to increased cardiac mammalian target of rapamycin complex 1 (mTORC1) signaling and endoplasmic reticulum (ER) stress. Transthoracic echocardiography showed decreased cardiac function in fld mice; however, cardiac dysfunction was not observed in ex vivo perfused working fld hearts. This showed that changes in systemic factors due to the global absence of lipin-1 could contribute to the decreased cardiac function in vivo. Collectively, this study shows that fld hearts exhibit unchanged oleate esterification, as well as oleate and glucose oxidation, despite the absence of lipin-1. However, lipin-1 deficiency increases the accumulation of newly synthesized phosphatidate and induces aberrant cell signaling.

Histopathologic and immunohistochemical lesions in liver of mink infected with Aleutian disease virus

Parvovirus of Aleutian disease causes mainly damage to kidneys, but immune complexes deposition and damage may occur also in other organs. In mink farms of Latvia the liver dystrophy or hepatic lipidosis of mink is widely distributed. The goal of this study was to examine probability of liver damage and regeneration of mink infected with Aleutian disease virus. Liver injury was assessed histologically. The mink liver demonstrated inflammation of liver parenchyma and foci of fatty liver. In immunohistochemistry, during liver regeneration the matrix metalloproteinases MMP-9, vascular endothelial growth factor and beta-defensin 2 expressions were lower, but MMP-2 and nerve growth factor receptor p75 expression was increased.

Liver regeneration is impaired in lipodystrophic fatty liver dystrophy mice

We previously reported that mice subjected to partial hepatectomy exhibit rapid development of hypoglycemia followed by transient accumulation of fat in the early regenerating liver. We also showed that disrupting these metabolic alterations results in impaired liver regeneration. The studies reported here were undertaken to further characterize and investigate the functional importance of changes in systemic adipose metabolism during normal liver regeneration. The results showed that a systemic catabolic response is induced in each of two distinct, commonly used experimental models of liver regeneration (partial hepatectomy and carbon tetrachloride treatment), and that this response occurs in proportion to the degree of induced hepatic insufficiency. Together, these observations suggest that catabolism of systemic adipose stores may be essential for normal liver regeneration. To test this possibility, we investigated the hepatic regenerative response in fatty liver dystrophy (fld) mice, which exhibit partial lipodystrophy and have diminished peripheral adipose stores. The results showed that the development of hypoglycemia and hepatic accumulation of fat was attenuated and liver regeneration was impaired following partial hepatectomy in these animals. The fld mice also exhibited increased hepatic p21 expression and diminished plasma levels of the adipose-derived hormones adiponectin and leptin, which have each been implicated as regulators of liver regeneration. These data suggest that the hypoglycemia that develops after partial hepatectomy induces systemic lipolysis followed by accumulation of fat derived from peripheral stores in the early regenerating liver, and that these events may be essential for initiation of normal liver regeneration.

Insulin-stimulated Interaction with 14-3-3 Promotes Cytoplasmic Localization of Lipin-1 in Adipocytes

Lipin-1 is a bifunctional protein involved in lipid metabolism and adipogenesis. Lipin-1 plays a role in the biosynthesis of triacylglycerol through its phosphatidate phosphatase activity and also acts as a transcriptional co-activator of genes involved in oxidative metabolism. Lipin-1 resides in the cytoplasm and translocates to the endoplasmic reticulum membrane to catalyze the phosphatidate phosphatase reaction. It also possesses a nuclear localization signal, which is required for its translocation to the nucleus and may therefore be important for lipin-1 co-activator function. Thus, subcellular localization may be an important factor in the regulation of this protein. Here, we show that the nuclear localization signal alone is not sufficient for lipin-1 nuclear localization, and identify lipin-1 interaction with 14-3-3 as a determinant of its subcellular localization. We demonstrate that lipin-1 interacts with 14-3-3 proteins and that overexpression of 14-3-3 promotes the cytoplasmic localization of lipin-1 in 3T3-L1 adipocytes. The effect of 14-3-3 is mediated through a serine-rich domain in lipin-1. Functional mapping of the 14-3-3-interacting region within the serine-rich domain indicates redundancy and cooperativity among several sites, including five phosphorylated serine and threonine residues. Insulin stimulation of 3T3-L1 adipocytes results in increased lipin-1 phosphorylation, enhanced interaction with 14-3-3, and predominantly cytoplasmic localization. In summary, our studies suggest that insulin may modulate the cellular function of lipin-1 by regulating its subcellular localization through interactions with 14-3-3 proteins.

The level and compartmentalization of phosphatidate phosphatase-1 (lipin-1) control the assembly and secretion of hepatic VLDL

Phosphatidate phosphatase-1 (PAP-1) converts phosphatidate to diacylglycerol and plays a key role in the biosynthesis of phospholipids and triacylglycerol (TAG). PAP-1 activity is encoded by members of the lipin family, including lipin-1 (1alpha and 1beta), -2, and -3. We determined the effect of lipin-1 expression on the assembly and secretion of very low density lipoproteins (VLDL) using McA-RH7777 cells. Expression of lipin-1alpha or -1beta increased the synthesis and secretion of [(3)H]glycerol-labeled lipids under either basal- or oleate-supplemented conditions. In the presence of oleate, the increased TAG secretion was mainly associated with VLDL(1) (S(f) > 100) and VLDL(2) (S(f) 20-100). Expression of lipin-1alpha or -1beta increased secretion efficiency and decreased intracellular degradation of [(35)S]apolipoprotein B-100 (apoB100). Knockdown of lipin-1 using specific short interfering RNA decreased secretion of [(3)H]glycerolipids and [(35)S]apoB100 even though total PAP-1 activity was not decreased, owing to the presence of lipin-2 and -3 in the cells. Deletion of the nuclear localization signal sequences within lipin-1alpha not only abolished nuclear localization but also resulted in impaired association with microsomal membranes. Cells expressing the cytosolic lipin-1alpha mutant failed to promote [(35)S]apoB100 synthesis or secretion, and showed compromised stimulation in [(3)H]TAG synthesis and secretion. Thus, alteration in hepatic expression of lipin-1 and its compartmentalization control VLDL assembly/secretion.

LPIN1 genetic variation is associated with rosiglitazone response in type 2 diabetic patients

Lipin1 protein, a product of the LPIN1 gene, is required for normal adipose tissue development and metabolism. Lipin1 deficiency results in immature adipocyte development in cases of mouse fatty liver dystrophy and human lipodystrophy. Recently, pioglitazone has been reported to increase human adipocyte lipin1 expression. We evaluated the effects of LPIN1 polymorphisms on rosiglitazone response in patients with type 2 diabetes (T2DM). A total of 262 patients were treated with 12 weeks of rosiglitazone (4 mg/day) in addition to their previous drug regimen medications. Six single nucleotide polymorphisms (SNPs) at the LPIN1 locus were genotyped: rs11693809, rs10192566, rs2278513, rs2577262, rs2716610, and rs1050800. Because rs11693809, rs10192566, and rs2278513 are in nearly complete linkage disequilibrium (D′ > 0.958, r 2 > 0.882), we analyzed rs10192566, rs2577262, rs2716610, and rs1050800. Rs10192566 was significantly associated with rosiglitazone treatment response. Patients with the G allele in rs10192566 had a larger decrease in fasting plasma glucose, 2-h postprandial glucose, and HbA1c than those without. This genetic effect remained significant after adjustment for age, sex, and initial body weight. No other SNPs were associated with response. These data suggest that LPIN1 genetic variations can affect rosiglitazone treatment response in T2DM.