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oils rich in alpha-linolenic acid independently protect against characteristics of fatty liver disease in the delta-6 desaturase mouseMonteiro, Jessica 24 August 2012 (has links)
The biological activity of α-linolenic acid (ALA) is poorly understood and primarily associated with its conversion to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). This study used the Δ6 desaturase knockout (D6KO) mouse, which lacks Δ6 desaturase and therefore cannot convert ALA, to evaluate the independent effects of ALA on preventing non-alcoholic fatty liver disease (NAFLD). First, the capacity of very long chain fatty acids to rescue the D6KO lipid profile was established. Next, to evaluate the independent effects of ALA, D6KO or wild-type mice were fed diets containing lard, canola, flaxseed, or fish oil. Following treatment, liver phospholipid fatty acid composition was evaluated and livers were scored for steatosis and inflammation. Glucose tolerance was also evaluated. D6KO mice fed ALA-rich diets had lower liver lipid accumulation, lower hepatic inflammation (8 weeks) and improved glucose tolerance (20 weeks) relative to lard-fed D6KO mice. Overall, this thesis supports an independent biological role for ALA. / D.W.L. Ma is funded by the Canola Council of Canada, Natural Sciences and Engineering Research Council of Canada and the Canada Foundation for Innovation Leaders Opportunity Fund with matching from the Ontario Research Fund; Jessica Monteiro is funded Ontario Graduate Scholarship.
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Characterization of Phosphatidylcholine Metabolism in Mouse Hepatocytes after Hepatectomy and in Primary Human HepatocytesLing, Ji Unknown Date
No description available.
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THE ABSENCE OF ABCD2 REVEALS A NOVEL ROLE FOR PEROXISOMES IN THE PROTECTION FROM METABOLIC SYNDROMELiu, Jingjing 01 January 2011 (has links)
ABCD2 (D2) is a peroxisomal ATP binding cassette (ABC) transporter that is expressed in brain, adrenal and liver. D2 is transcriptionally regulated by key transcriptional factors that control lipid and glucose metabolism. Therefore, we examined its role in adipose tissue. These studies revealed that D2 is highly abundant in adipose tissue and upregulated during adipogenesis. However, D2 deficiency does not affect either adipogenesis or lipid accumulation. An examination of the lipid profile of adipose tissue revealed the accumulation of C20 and C22 fatty acids in D2 deficient (D2‐/‐) mice. When challenged with a diet enriched in erucic acid (C22:1, 10% kcal), this lipid accumulated in both liver and adipose tissue. Following 8 weeks of diet, D2‐/‐ mice showed increased adiposity, glucose intolerance, dyslipidemia and steatosis. Analysis of the hepatic lipid profile showed significant changes away from poly unsaturated fatty acids (PUFAs) and toward C18‐22 mono‐unsaturated fatty acids (MUFA). RT‐PCR of the mRNA from the adipose tissue and liver revealed significant changes in lipogenic (ACC, SCD1 & 2) and PUFA synthesis (Δ5 & 6‐desaturase) genes in D2‐/‐ mice. The molecular mechanisms by which D2 regulates lipid metabolism in adipose tissue remains unclear. To explore potential mechanisms, the subcellular localization of D2 in adipose tissue was determined. Our results demonstrated that D2 resides in a distinct subclass of peroxisomes that does not containing classical peroxisomal markers such as pex19 or PMP70, but are positive for pex14. In conclusion, our studies reveal a novel role of D2 and peroxisomes in the protection from disruptions of lipid metabolism induced by dietary erucic acid and that D2 resides in a unique compartment within adipocytes that plays a yet to be elucidated role in the regulation of lipid metabolism.
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Investigating the Associations of Coffee with Non-traditional Risk Factors for Type 2 Diabetes MellitusDickson, Jolynn Catherine 21 November 2012 (has links)
Coffee consumption has consistently been associated with a reduction in risk of type 2 diabetes mellitus (T2DM), although the mechanism for this association remains unknown. Sub-clinical inflammation, non-alcoholic fatty liver disease (NAFLD), and lipoprotein abnormalities characterize and predict T2DM. Limited evidence suggests that coffee may have a beneficial role in these disorders but further investigation is warranted. Our aim therefore was to investigate the associations of caffeinated and decaffeinated coffee with markers of inflammation, liver injury, and lipoproteins, in a non-diabetic cohort. No significant associations of caffeinated or decaffeinated coffee with inflammatory markers or lipoproteins were identified. Caffeinated coffee consumption however was inversely associated with alanine aminotransferase (β= -0.09, p= 0.0107) and aspartate aminotransferase (β= -0.05, p= 0.0161) in multivariate analysis. Decaffeinated coffee was not associated with liver enzymes. These analyses suggest that caffeinated coffee’s beneficial impact on NAFLD may be a potential mechanism for its inverse association with T2DM.
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Investigating the Associations of Coffee with Non-traditional Risk Factors for Type 2 Diabetes MellitusDickson, Jolynn Catherine 21 November 2012 (has links)
Coffee consumption has consistently been associated with a reduction in risk of type 2 diabetes mellitus (T2DM), although the mechanism for this association remains unknown. Sub-clinical inflammation, non-alcoholic fatty liver disease (NAFLD), and lipoprotein abnormalities characterize and predict T2DM. Limited evidence suggests that coffee may have a beneficial role in these disorders but further investigation is warranted. Our aim therefore was to investigate the associations of caffeinated and decaffeinated coffee with markers of inflammation, liver injury, and lipoproteins, in a non-diabetic cohort. No significant associations of caffeinated or decaffeinated coffee with inflammatory markers or lipoproteins were identified. Caffeinated coffee consumption however was inversely associated with alanine aminotransferase (β= -0.09, p= 0.0107) and aspartate aminotransferase (β= -0.05, p= 0.0161) in multivariate analysis. Decaffeinated coffee was not associated with liver enzymes. These analyses suggest that caffeinated coffee’s beneficial impact on NAFLD may be a potential mechanism for its inverse association with T2DM.
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Avaliação clínica, laboratorial e dos marcadores bioquímicos do estresse oxidativo hepatocelular em ratos diabéticos induzidos pela aloxana /Lucchesi, Amanda Natália. January 2010 (has links)
Orientador: César Tadeu Spadella / Banca: José Guilherme Minossi / Banca: Silvio Fernando Guideti Marques / Resumo: O diabetes mellitus (DM) é tido como um problema de saúde pública mundial. No Brasil ele atinge mais de 14 milhões de pessoas, sendo acompanhado de altos índices de morbidade e mortalidade. Entretanto, os mecanismos primariamente responsáveis pela agressão dos tecidos e órgãos pelo DM ainda não são completamente conhecidos, o que explica a dificuldade em se estabelecer um tratamento eficaz para prevenir ou controlar a progressão das lesões diabéticas crônicas. O estresse oxidativo celular é tido como um dos mecanismos importantes na gênese do dano tecidual relacionado à hiperglicemia. Através deste mecanismo, o DM poderia aumentar a produção de espécies reativas do oxigênio (EROs) ao nível celular, que pela sua toxicidade, seria capaz de promover o desenvolvimento das lesões diabéticas crônicas. Evidências clínicas sugerem que o fígado de indivíduos diabéticos também poderia sofrer a ação das EROs, no longo prazo, levando a uma seqüência de eventos capaz de determinar a doença gordurosa do fígado de etiologia não-alcoólica (DGFNA), com progressão para esteato-hepatite e cirrose. Todavia, a presença de estresse oxidativo no tecido hepático de portadores de DM, ainda não está bem estabelecida na literatura, o que justifica a realização de novas investigações em modelos-animais de diabetes, no intuito de melhor esclarecer a real participação deste mecanismo na gênese e evolução das lesões hepáticas diabéticas crônicas. Neste estudo foram utilizados 60 ratos machos Lewis, distribuídos em 2 grupos experimentais, com 30 animais cada um, assim designados: GN - Grupo Controle: constituído de ratos normais, não-diabéticos; GD - Grupo Diabético: constituído por animais diabéticos induzidos pela aloxana, sem qualquer tratamento. Cada um dos grupos experimentais foi dividido em 3 subgrupos de ratos, com 10 animais cada um, para serem... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Diabetes mellitus (DM) is considered to be a public-health problem worldwide. In Brazil, it affects 14 million people, and it is accompanied by high morbidity and mortality rates. However, the mechanisms primarily responsible for tissue and organ aggression by DM are not yet fully known, which explains the difficulty in establishing effective treatment to prevent or control the progression of chronic diabetic lesions. Cellular oxidative stress is considered to be one of the important mechanisms in the genesis of hyperglycemia-related tissue damage. Through this mechanism, DM could increase the production of reactive oxygen species (ROS) in the cellular level, which, due to their toxicity, could promote the development of chronic diabetic lesions. Clinical evidence suggests that the liver of diabetic individuals could also suffer the action of ROS in the long term, thus leading to a sequence of events that can determine non-alcoholic fatty liver disease (NAFLD), with progression to steatohepatitis and cirrhosis. However, the presence of oxidative stress in the hepatic tissue of individuals with DM has not been yet well established in the literature, which justifies the performance of new investigations in diabetes animal models with the purpose to clarify the actual participation of such mechanisms in the genesis and development of chronic diabetic hepatic lesions. In this study, 60 males Lewis rats were used. They were distributed into 2 experimental groups, each containing 30 animals and designated as follows: GN - Control Group: consisting of non-diabetic control rats; GD - Diabetic Group: consisting of alloxan-induced diabetic rats without any treatment. Each experimental group was divided into 3 subgroups of rats with 10 animals each to be evaluated and sacrificed respectively at 4 experimental moments, namely: M1- animals from the 3 subgroups, at the initial moment... (Complete abstract click electronic access below) / Mestre
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Investigating the role of lipocalin-2 as a diagnostic indicator for nonalcoholic steatohepatitis in a fructose-induced rat fatty liver model: First experimental studiesAlwahsh, Salamah Mohammad 12 December 2013 (has links)
No description available.
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THE ROLE OF PROLACTIN RECEPTOR SIGNALING IN LIVER HOMEOSTASIS AND DISEASEJennifer Abla Yanum (11157624) 06 August 2021 (has links)
<p>Functioning as a “powerhouse”, the liver adapts to the
metabolic needs of the body by maintaining a homeostatic balance. Prolactin
receptor (PRLR) has been found
to have a copious existence in the liver. Having established a well-defined role in both reproductive
and endocrine systems, the role of this transmembrane protein in hepatocytes is
yet to be elucidated. Due to its abundant nature, we hypothesized that PRLR is
required for maintaining hepatic homeostasis and plays a role in liver
diseases. To test this hypothesis, we defined two specific aims. The first was
to explore whether PRLR loss-of-function affects liver structure and function
in physiological conditions. The second was to determine whether PRLR is
associated with liver pathology. We deleted the <i>Prlr</i> gene specifically in hepatocytes using a virus-based approach
and evaluated liver function, transcriptome, and activities of downstream signaling
molecules. Due to the absence of PRLR, we found that the urea cycle was
disrupted, concomitant with excessive accumulation of urea in the blood; 133 genes exhibited
differential expression, largely associated with hepatocyte structure,
metabolism, and inflammation; and the activities of STAT3 and 5 were reduced. The
results signify that PRLR indeed plays a homeostatic role in the liver. We also
used <i>Prlr</i><sup>+/-</sup> mice to
assess whether the loss of one allele of the <i>Prlr</i> gene alters maternal hepatic adaptations to pregnancy. As a
result, in the pre-pregnancy state and during the first half of gestation, the
expression of maternal hepatic PRLR protein was reduced approximately by half
owing to <i>Prlr</i> insufficiency. However,
during the second half of pregnancy, we observed compensatory upregulation of
this molecule, leading to minimal
interference in
STAT 3 and 5 signaling and liver size. Contrary to a previous study in the
breast and ovary, our results suggest that one allele of <i>Prlr</i> may be sufficient for the maternal liver to respond to this physiological
stimulus (pregnancy). Furthermore, we examined the expression and activity of
PRLR in fatty as well as cholestatic livers. Using a high fat diet, we induced non-alcoholic
fatty liver disease (NAFLD).
Strikingly and for the first time, we discovered that the short isoform of PRLR
(PRLR-S) was completely inactivated in response to NAFLD, whereas the long isoform
remained unchanged. This finding strongly suggests the involvement of PRLR-S in
lipid metabolism. We also postulate that PRLR-L may be the major regulator of
STAT signaling in the liver, consistent with other reports. Lastly, we induced
extrahepatic cholestasis via bile duct ligation (BDL) in mice. As this liver
disease progressed, the expression of both isoforms of PRLR generally declined
and was surprisingly accompanied by increased STAT 3 and 5 activity. The data
suggests that PRLR participates in this disease progression, with a
disconnection between PRLR signaling and STAT proteins. Collectively, our preliminary
studies suggest that PRLR signaling is required to maintain liver homeostasis
and more prominently, is involved in liver diseases, especially NAFLD. These
findings lay a foundation for our future studies.</p>
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The Role of Prolactin Receptor Signaling in Liver Homeostasis and DiseaseYanum, Jennifer Alba 08 1900 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Functioning as a “powerhouse”, the liver adapts to the metabolic needs of the body by maintaining a homeostatic balance. Prolactin receptor (PRLR) has been found to have a copious existence in the liver. Having established a well-defined role in both reproductive and endocrine systems, the role of this transmembrane protein in hepatocytes is yet to be elucidated. Due to its abundant nature, we hypothesized that PRLR is required for maintaining hepatic homeostasis and plays a role in liver diseases. To test this hypothesis, we defined two specific aims. The first was to explore whether PRLR loss-of-function affects liver structure and function in physiological conditions. The second was to determine whether PRLR is associated with liver pathology. We deleted the Prlr gene specifically in hepatocytes using a virus-based approach and evaluated liver function, transcriptome, and activities of downstream signaling molecules. Due to the absence of PRLR, we found that the urea cycle was disrupted, concomitant with excessive accumulation of urea in the blood; 133 genes exhibited differential expression, largely associated with hepatocyte structure, metabolism, and inflammation; and the activities of STAT3 and 5 were reduced. The results signify that PRLR indeed plays a homeostatic role in the liver. We also used Prlr+/- mice to assess whether the loss of one allele of the Prlr gene alters maternal hepatic adaptations to pregnancy. As a result, in the pre-pregnancy state and during the first half of gestation, the expression of maternal hepatic PRLR protein was reduced approximately by half owing to Prlr insufficiency. However, during the second half of pregnancy, we observed compensatory upregulation of this molecule, leading to minimal interference in STAT 3 and 5 signaling and liver size. Contrary to a previous study in the breast and ovary, our results suggest that one allele of Prlr may be sufficient for the maternal liver to respond to this physiological stimulus (pregnancy). Furthermore, we examined the expression and activity of PRLR in fatty as well as cholestatic livers. Using a high fat diet, we induced non-alcoholic fatty liver disease (NAFLD). Strikingly and for the first time, we discovered that the short isoform of PRLR (PRLR-S) was completely inactivated in response to NAFLD, whereas the long isoform remained unchanged. This finding strongly suggests the involvement of PRLR-S in lipid metabolism. We also postulate that PRLR-L may be the major regulator of STAT signaling in the liver, consistent with other reports. Lastly, we induced extrahepatic cholestasis via bile duct ligation (BDL) in mice. As this liver disease progressed, the expression of both isoforms of PRLR generally declined and was surprisingly accompanied by increased STAT 3 and 5 activity. The data suggests that PRLR participates in this disease progression, with a disconnection between PRLR signaling and STAT proteins. Collectively, our preliminary studies suggest that PRLR signaling is required to maintain liver homeostasis and more prominently, is involved in liver diseases, especially NAFLD. These findings lay a foundation for our future studies.
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MICROBIAL METABOLISM OF DIETARY INPUT IN CARDIOMETABOLICDISEASE PATHOGENESISOsborn, Lucas Jerry 01 September 2021 (has links)
No description available.
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