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David Q.-h. Wang - One of the best experts on this subject based on the ideXlab platform.

  • The deletion of the estrogen receptor α gene reduces susceptibility to estrogen-induced cholesterol cholelithiasis in female mice.
    Biochimica et biophysica acta, 2015
    Co-Authors: Ornella De Bari, Helen H. Wang, Piero Portincasa, Min Liu, David Q.-h. Wang
    Abstract:

    Compelling evidence has demonstrated that estrogen is a critical risk factor for gallstone formation and enhances cholesterol cholelithogenesis through the hepatic estrogen receptor α (ERα), but not ERβ. To study the Lithogenic mechanisms of estrogen through ERα, we investigated whether the deletion of Erα protects against gallstone formation in ovariectomized (OVX) female mice fed a Lithogenic Diet and treated with 17β-estradiol (E2) at 0 or 6μg/day for 56days. Our results showed that the prevalence of gallstones was reduced from 100% in OVX ERα (+/+) mice to 30% in OVX ERα (-/-) mice in response to high doses of E2 and the Lithogenic Diet for 56days. Hepatic cholesterol secretion was significantly diminished in OVX ERα (-/-) mice compared to OVX ERα (+/+) mice even fed the Lithogenic Diet and treated with E2 for 56days. These alterations decreased bile Lithogenicity by reducing cholesterol saturation index of gallbladder bile. Immunohistochemical studies revealed that ERα was expressed mainly in the gallbladder smooth muscle cells. High levels of E2 impaired gallbladder emptying function mostly through the ERα and cholecystokinin-1 receptor pathway, leading to gallbladder stasis in OVX ERα (+/+) mice. By contrast, gallbladder emptying function was greatly improved in OVX ERα (-/-) mice. This markedly retarded cholesterol crystallization and the growth and agglomeration of solid cholesterol crystals into microlithiasis and stones. In conclusion, the deletion of Erα reduces susceptibility to the formation of E2-induced gallstones by diminishing hepatic cholesterol secretion, desaturating gallbladder bile, and improving gallbladder contraction function in female mice.

  • Evidence that gallbladder epithelial mucin enhances cholesterol cholelithogenesis in MUC1 transgenic mice.
    Gastroenterology, 2006
    Co-Authors: Helen H. Wang, Nezam H. Afdhal, Sandra J. Gendler, David Q.-h. Wang
    Abstract:

    Background & Aims: The gel-forming mucins play an important role in the early stage of cholesterol gallstone formation. We investigated whether the gallbladder epithelial mucin encoded by mucin gene 1 (MUC1) influences susceptibility to gallstones. Methods: Gallbladder motility and cholesterol absorption, gallstones and expression of the mucin genes in gallbladders, and secretion rates and compositions of biliary lipids were determined in male C57BL/6J mice transgenic for the human MUC1 gene (MUC1.Tg) and wild-type mice before (day 0, on chow) and at 4 weeks on a Lithogenic Diet containing 1% cholesterol and 0.5% cholic acid. Results: On chow, expression levels of the gallbladder mucin genes were essentially similar between MUC1.Tg and wild-type mice. The Lithogenic Diet induced 3-fold higher expression levels of Muc1, Muc3, Muc4, Muc5ac, and Muc5b messenger RNA in MUC1.Tg mice compared with wild-type mice. Gallbladder cholesterol absorption and size were significantly greater in MUC1.Tg mice than in wild-type mice regardless of whether the chow or the Lithogenic Diet was fed. Gallbladder emptying in response to exogenously administered cholecystokinin-8 was significantly reduced in MUC1.Tg mice but not in wild-type mice. At 4 weeks on the Lithogenic Diet, mucin accumulation was found in all MUC1Tg mice and in 60% of wild-type mice. Consequently, these alterations greatly accelerated cholesterol crystallization and gallstone formation in MUC1.Tg mice. However, biliary lipid secretion rates and cholesterol saturation indices of gallbladder biles were comparable in MUC1.Tg and wild-type mice. Conclusions: Increased gallbladder epithelial MUC1 mucin enhances cholelithogenesis by promoting gallbladder cholesterol absorption and impairing gallbladder motility in mice.

  • gallbladder histopathology during murine gallstone formation relation to motility and concentrating function
    Journal of Lipid Research, 2006
    Co-Authors: Karel J Van Erpecum, David Q.-h. Wang, Piero Portincasa, Antonio Moschetta, Domenico Ferri, Maria Svelto, Janjaap Hendrickx, Marguerite E I Schipper, Giuseppe Calamita
    Abstract:

    C57L mice are susceptible and AKR mice art resistant to gallstone formation. We studied in male mice of both strains gallbladder histopathology, cholecystokinin-induced emptying, and concentrating function at 0, 14, 28 and 56 days on a Lithogenic Diet. Gallbladder wall thickness increased on the Diet, with stromal granulocyte infiltration, progressive fibrosis, edema, and epithelial cell indentation, particularly in C57L. Strong basal cholecys tokinin octapeptide-induced gallbladder emptying (70% oi fasting volumes) occurred in both strains, but fasting gallbladder volumes were significantly larger in C57L (14.8 ± 2.2 μl vs. 8.8 ± 1.0 μl). On the Diet, fasting volumes in creased exclusively in C57L (28.6 ± 2.9 μl on day 56), with progressively decreased emptying (27% of fasting volumes on day 56). Gallbladder emptying remained normal in AKR. Gallbladder concentrating function decreased on the Lithogenic Diet (especially in C57L), coinciding with decreased aquaporin-1 (AQP1) and AQP8 expression at the mRNA and protein levels. In additional experiments, similai downregulation of AQP1 and AQP8 mRNA expression occurred in farnesoid X receptor (FXR)-defident mice aftei 1 week on the Lithogenic Diet, without any difference from corresponding wild-type mice. In conclusion, during murine lithogenesis, altered gallbladder histology is associated with impaired motility, reduced concentrating function, and decreased AQP1 and AQP8 expression, the latter without the involvement of the FXR.-van Erpecum, K. J., D. Q-H. Wang, A. Moschetta, D. Fern, M. Svelto, P. Portincasa, J-J. Hendrickx, M. Schipper, and G. Calamita. Gallbladder histopathology during murine gallstone formation: relation to motility and concentrating function.

  • Reduced susceptibility to cholesterol gallstone formation in mice that do not produce apolipoprotein B48 in the intestine
    Hepatology (Baltimore Md.), 2005
    Co-Authors: Helen H. Wang, David Q.-h. Wang
    Abstract:

    It has been found that polymorphisms in the apolipoprotein (APO)-B gene are associated with cholesterol gallstones in humans. We hypothesized that APO-B plays a major regulatory role in the response of biliary cholesterol secretion to high Dietary cholesterol and contributes to cholesterol gallstone formation. In the present study, we investigated whether lack of expression of intestinal Apob48 or Apob100 reduces susceptibility to cholesterol gallstones by decreasing intestinal absorption and biliary secretion of cholesterol in male mice homozygous for an "APO-B48 only" allele (Apob(48/48)), an "APO-B100 only" allele (Apob(100/100)), or a wild-type APO-B allele (Apob+/+) before and during an 8-week Lithogenic Diet. We found that cholesterol absorption was significantly decreased as a result of the APO-B48 deficiency in Apob(100/100) mice compared with wild-type and Apob(48/48) mice, regardless of whether chow or the Lithogenic Diet was administered. Consequently, hepatic cholesterol synthesis was significantly increased in Apob(100/100) mice compared with wild-type and Apob(48/48) mice. On chow, the APO-B100 deficiency in Apob(48/48) mice with reduced plasma levels of LDL/VLDL--but not HDL cholesterol--induced relative hyposecretion of biliary bile salts and phospholipids accompanying normal biliary cholesterol secretion. Compared with Apob(48/48) and wild-type mice, Lithogenic Diet-fed Apob(100/100) mice displayed significantly lower secretion rates of biliary cholesterol, but not phospholipid or bile salts, which results in significant decreases in prevalence rates, numbers, and sizes of gallstones. In conclusion, absence of expression of intestinal Apob48, but not Apob100, reduces biliary cholesterol secretion and cholelithogenesis, possibly by decreasing intestinal absorption and hepatic bioavailability.

  • Susceptibility to murine cholesterol gallstone formation is not affected by partial disruption of the HDL receptor SR-BI.
    Biochimica et biophysica acta, 2002
    Co-Authors: David Q.-h. Wang, Martin C. Carey
    Abstract:

    Abstract High density lipoprotein (HDL) promotes reverse cholesterol transport from peripheral tissues to the liver where its cholesterol is secreted preferentially into bile. The scavenger receptor class B type I (SR-BI) is believed to play a pivotal role in unloading HDL cholesterol and its ester to hepatocytes. Here, using male SR-BI “att” mice with a dysfunctional mutation in the Sr-b1 promoter, we studied whether ∼50% of normal SR-BI expression influences gallstone susceptibility in these mice fed a Lithogenic Diet containing 1% cholesterol, 0.5% cholic acid and 15% butterfat. Our results showed that the disruption of SR-BI expression reduced cholesterol secretion by 37% in the chow-fed state and 10% on the Lithogenic Diet, and while delaying incidence slightly, did not influence cumulative susceptibility to cholesterol gallstones. The Lithogenic Diet induced marked increases in biliary cholesterol and phospholipid secretion rates but not of bile salts. Basal expression of hepatic SR-BI protein was dissimilar in both wild-type and SR-BI mice, and remained unaltered in response to the Lithogenic Diet. By two independent dual isotope methods, intestinal cholesterol absorption was unimpaired by attenuation of the SR-BI which also displays low-density expression on small intestinal enterocytes. We conclude that although HDL cholesterol is a principal source of biliary cholesterol in the basal state, uptake of cholesterol from chylomicron remnants appears to be the major contributor to biliary cholesterol hypersecretion during Diet-induced cholelithogenesis in the mouse.

Yu Tian - One of the best experts on this subject based on the ideXlab platform.

  • phosphorylation and subcellular localization of na h exchanger isoform 3 nhe3 are associated with altered gallbladder absorptive function after formation of cholesterol gallstones
    Journal of Physiology and Biochemistry, 2017
    Co-Authors: Yongsheng Chen, Yu Tian, Jing Kong
    Abstract:

    Na+/H+ exchanger isoform 3 (NHE3) dysfunction is thought to contribute to the altered gallbladder absorption that occurs in cholesterol gallstone disease, but the mechanism is unknown. The current study was undertaken to examine the expression, phosphorylation, and subcellular localization of NHE3 in gallbladder epithelium cells (GBECs) of male C57BL/6 mice on a control or Lithogenic Diet. Thirty-six 8-week-old male C57BL/6 mice were randomly assigned to receive a high cholesterol Diet or a regular Diet for 8 weeks. Gallstone formation was recorded. Gallbladder bile cholesterol, phospholipid, and total bile acids were examined. RT-PCR was used to measure NHE3 mRNA expression. NHE3 protein expression and subcellular localization were examined by Western blotting and immunofluorescence microscopy, respectively. Gallstones were formed in all mice fed the Lithogenic Diet. Despite higher NHE3 mRNA expression in gallbladders of the mice on the Lithogenic Diet than in those on the control Diet, there was no significant difference in expression of total NHE3 protein. However, a higher level of NHE3 phosphorylated at serine-552 (P-NHE3) was seen on the Lithogenic Diet. In immunofluorescence studies, NHE3 protein was expressed both on the apical membrane and in the cytoplasm of mouse GBEC. This pattern of subcellular distribution of NHE3 strongly corroborates an exchanger trafficking mechanism in NHE3 activity regulation in mouse GBEC. We conclude that increased phosphorylation of NHE3 following gallstone formation leads to turnover of the exchanger, resulting in decreased gallbladder concentrating function.

  • Combination of curcumin and piperine prevents formation of gallstones in C57BL6 mice fed on Lithogenic Diet: whether NPC1L1/SREBP2 participates in this process?
    Lipids in Health and Disease, 2015
    Co-Authors: Yongnan Li, Min Li, Shuodong Wu, Yu Tian
    Abstract:

    A disruption of cholesterol homeostasis characterized by the physical-chemical imbalance of cholesterol solubility in bile often results in formation of cholesterol gallstones. Our earlier studies revealed that curcumin (1000 mg/kg) could prevent formation of gallstones. It has been proved that curcumin is poorly absorbed while piperine is a bioavailability-enhancer. Nevertheless, whether curcumin combined with piperine could enhance the effect of curcumin in preventing gallstones is still awaited. C57BL6 mice were fed on a Lithogenic Diet concomitant with curcumin at 500 or 1000 mg/kg and/or piperine at 20 mg/kg for 4 weeks. The ratio of gallbladder stone formation was recorded and samples of blood, bile, gallbladder, liver and small intestine were also collected. The volume of gallbladder and weight of liver were calculated, and blood and bile samples were analyzed through biochemical methods. Intestinal NPC1L1 and SREBP2 mRNA and protein expression were detected by real-time PCR and Western blot. Combining with piperine can significantly enhance the effect of curcumin, thus preventing the development of gallbladder stones, lowering the saturation of blood lipids and cholesterol in bile, as well as decreasing the expression of NPC1L1 and SREBP2 in both mRNA and protein levels. Curcumin can prevent the formation of cholesterol gallstones induced by high fat Diet in mice and SREBP2 and NPC1L1 may participate in this process. Piperine can increase curcumin’s bioavailability, thereby enhancing the effect of curcumin.

  • combination of curcumin and piperine prevents formation of gallstones in c57bl6 mice fed on Lithogenic Diet whether npc1l1 srebp2 participates in this process
    Lipids in Health and Disease, 2015
    Co-Authors: Yongnan Li, Min Li, Shuodong Wu, Yu Tian
    Abstract:

    A disruption of cholesterol homeostasis characterized by the physical-chemical imbalance of cholesterol solubility in bile often results in formation of cholesterol gallstones. Our earlier studies revealed that curcumin (1000 mg/kg) could prevent formation of gallstones. It has been proved that curcumin is poorly absorbed while piperine is a bioavailability-enhancer. Nevertheless, whether curcumin combined with piperine could enhance the effect of curcumin in preventing gallstones is still awaited. C57BL6 mice were fed on a Lithogenic Diet concomitant with curcumin at 500 or 1000 mg/kg and/or piperine at 20 mg/kg for 4 weeks. The ratio of gallbladder stone formation was recorded and samples of blood, bile, gallbladder, liver and small intestine were also collected. The volume of gallbladder and weight of liver were calculated, and blood and bile samples were analyzed through biochemical methods. Intestinal NPC1L1 and SREBP2 mRNA and protein expression were detected by real-time PCR and Western blot. Combining with piperine can significantly enhance the effect of curcumin, thus preventing the development of gallbladder stones, lowering the saturation of blood lipids and cholesterol in bile, as well as decreasing the expression of NPC1L1 and SREBP2 in both mRNA and protein levels. Curcumin can prevent the formation of cholesterol gallstones induced by high fat Diet in mice and SREBP2 and NPC1L1 may participate in this process. Piperine can increase curcumin’s bioavailability, thereby enhancing the effect of curcumin.

Martin C. Carey - One of the best experts on this subject based on the ideXlab platform.

  • Components of the biliary phenotype may be altered by crossfostering mice shortly after birth.
    2013
    Co-Authors: Jacqueline J. Fremont-rahl, Martin C. Carey, Carlos Umana, Mark T. Whary, Nancy S. Taylor, Sureshkumar Muthupalani, James G. Fox, Kirk J. Maurer
    Abstract:

    (A) Normalized gallbladder weight (B) mucin gel score (C) Liquid crystal phase separation (D) cholesterol monohydrate crystal formation, (E) sandy stone formation and (F) cholesterol gallstone formation were analyzed after 8 weeks of Lithogenic Diet feeding. (A) Both Tac and Jax fostered to Tac developed significantly larger gallbladders (*P

  • Biliary phenotype of genetically related BALB/cAnNTac (Tac) and BALB/cByJ (ByJ) and BALB/cJBomTac (Bom) and BALB/cJ (Jax) mice.
    2013
    Co-Authors: Jacqueline J. Fremont-rahl, Martin C. Carey, Carlos Umana, Mark T. Whary, Nancy S. Taylor, Sureshkumar Muthupalani, James G. Fox, Kirk J. Maurer
    Abstract:

    (A) Normalized gallbladder weight (B) mucin gel score (C) Liquid crystal phase separation (D) cholesterol monohydrate crystal formation, (E) sandy stone formation and (F) cholesterol gallstone formation were analyzed after 8 weeks of Lithogenic Diet feeding. (A) Normalized gallbladder weight significantly differed between Tac mice and both ByJ and Jackson mice (*P

  • disruption of gallbladder smooth muscle function is an early feature in the development of cholesterol gallstone disease
    Neurogastroenterology and Motility, 2012
    Co-Authors: Brigitte Lavoie, Martin C. Carey, Bernhard Nausch, E A Zane, Monika R Leonard, Onesmo B Balemba, Aaron C Bartoo, Rebecca Wilcox, Mark Nelson, Gary M Mawe
    Abstract:

    BACKGROUND; Decreased gallbladder smooth muscle (GBSM) contractility is a hallmark of cholesterol gallstone disease, but the interrelationship between Lithogenicity, biliary stasis, and inflammation are poorly understood. We studied a mouse model of gallstone disease to evaluate the development of GBSM dysfunction relative to changes in bile composition and the onset of sterile cholecystitis. METHODS: BALB/cJ mice were fed a Lithogenic Diet for up to 8 weeks, and tension generated by gallbladder muscle strips was measured. Smooth muscle Ca(2+) transients were imaged in intact gallbladder. KEY RESULTS: Lipid composition of bile was altered Lithogenically as early as 1 week, with increased hydrophobicity and cholesterol saturation indexes; however, inflammation was not detectable until the fourth week. Agonist-induced contractility was reduced from weeks 2 through 8. GBSM normally exhibits rhythmic synchronized Ca(2+) flashes, and their frequency is increased by carbachol (3 ?m). After 1 week, Lithogenic Diet-fed mice exhibited disrupted Ca(2+) flash activity, manifesting as clustered flashes, asynchronous flashes, or prolonged quiescent periods. These changes could lead to a depletion of intracellular Ca(2+) stores, which are required for agonist-induced contraction, and diminished basal tone of the organ. Responsiveness of Ca(2+) transients to carbachol was reduced in mice on the Lithogenic Diet, particularly after 4-8 weeks, concomitant with appearance of mucosal inflammatory changes. CONCLUSIONS & INFERENCES: These observations demonstrate that GBSM dysfunction is an early event in the progression of cholesterol gallstone disease and that it precedes mucosal inflammation.

  • W1379 A Cholesterol-Rich Diet But Not Enterohepatic Helicobacter Infection Prolongs Small Intestinal Transit in Mice
    Gastroenterology, 2008
    Co-Authors: Kirk J. Maurer, Bian Yu, Martin C. Carey
    Abstract:

    Introduction: Lithogenic Diet and infection with enterohepatic helicobacter are important for cholesterol gallstone formation in mice. Cholesterol gallstone formation in humans is associated with slowed intestinal transit, which increases cholesterol absorption and proLithogenic deoxycholate formation. Here we studied the effects of a Lithogenic Diet as well as enterohepatic helicobacter infection on small intestinal transit in inbred mice to determine if either or both promote prolonged small intestinal transit in mice. Methods: Male C57L/ J mice were infected with H. hepaticus or left uninfected and fed either a Lithogenic Diet (containing 15% dairy triglycerides, 1% cholesterol and 0.5% cholic acid) or standard mouse chow (

  • Susceptibility to murine cholesterol gallstone formation is not affected by partial disruption of the HDL receptor SR-BI.
    Biochimica et biophysica acta, 2002
    Co-Authors: David Q.-h. Wang, Martin C. Carey
    Abstract:

    Abstract High density lipoprotein (HDL) promotes reverse cholesterol transport from peripheral tissues to the liver where its cholesterol is secreted preferentially into bile. The scavenger receptor class B type I (SR-BI) is believed to play a pivotal role in unloading HDL cholesterol and its ester to hepatocytes. Here, using male SR-BI “att” mice with a dysfunctional mutation in the Sr-b1 promoter, we studied whether ∼50% of normal SR-BI expression influences gallstone susceptibility in these mice fed a Lithogenic Diet containing 1% cholesterol, 0.5% cholic acid and 15% butterfat. Our results showed that the disruption of SR-BI expression reduced cholesterol secretion by 37% in the chow-fed state and 10% on the Lithogenic Diet, and while delaying incidence slightly, did not influence cumulative susceptibility to cholesterol gallstones. The Lithogenic Diet induced marked increases in biliary cholesterol and phospholipid secretion rates but not of bile salts. Basal expression of hepatic SR-BI protein was dissimilar in both wild-type and SR-BI mice, and remained unaltered in response to the Lithogenic Diet. By two independent dual isotope methods, intestinal cholesterol absorption was unimpaired by attenuation of the SR-BI which also displays low-density expression on small intestinal enterocytes. We conclude that although HDL cholesterol is a principal source of biliary cholesterol in the basal state, uptake of cholesterol from chylomicron remnants appears to be the major contributor to biliary cholesterol hypersecretion during Diet-induced cholelithogenesis in the mouse.

Hiroshi Ohno - One of the best experts on this subject based on the ideXlab platform.

  • Absence of Elovl6 attenuates steatohepatitis but promotes gallstone formation in a Lithogenic Diet-fed Ldlr^−/− mouse model
    Scientific Reports, 2015
    Co-Authors: Motoko Kuba, Takashi Matsuzaka, Rie Matsumori, Ryo Saito, Naoko Kaga, Hikari Taka, Kei Ikehata, Naduki Okada, Takuya Kikuchi, Hiroshi Ohno
    Abstract:

    Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can develop into liver cirrhosis and cancer. Elongation of very long chain fatty acids (ELOVL) family member 6 (Elovl6) is a microsomal enzyme that regulates the elongation of C12–16 saturated and monounsaturated fatty acids (FAs). We have previously shown that Elovl6 plays an important role in the development of hepatic insulin resistance and NASH by modifying FA composition. Recent studies have linked altered hepatic cholesterol homeostasis and cholesterol accumulation to the pathogenesis of NASH. In the present study, we further investigated the role of Elovl6 in the progression of Lithogenic Diet (LD)-induced steatohepatitis. We showed that the absence of Elovl6 suppresses hepatic lipid accumulation, plasma total cholesterol and total bile acid (BA) levels in LDL receptor-deficient ( Ldlr ^−/−) mice challenged with a LD. The absence of Elovl6 also decreases hepatic inflammation, oxidative stress and liver injury, but increases the formation of cholesterol crystals in the less dilated gallbladder. These findings suggest that Elovl6-mediated changes in hepatic FA composition, especially oleic acid (C18:1n-9), control handling of hepatic cholesterol and BA, which protects against hepatotoxicity and steatohepatitis, but promotes gallstone formation in LD-fed Ldlr ^−/− mice.

  • Absence of Elovl6 attenuates steatohepatitis but promotes gallstone formation in a Lithogenic Diet-fed Ldlr −/− mouse model
    Scientific reports, 2015
    Co-Authors: Motoko Kuba, Takashi Matsuzaka, Rie Matsumori, Ryo Saito, Naoko Kaga, Hikari Taka, Kei Ikehata, Naduki Okada, Takuya Kikuchi, Hiroshi Ohno
    Abstract:

    Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can develop into liver cirrhosis and cancer. Elongation of very long chain fatty acids (ELOVL) family member 6 (Elovl6) is a microsomal enzyme that regulates the elongation of C12–16 saturated and monounsaturated fatty acids (FAs). We have previously shown that Elovl6 plays an important role in the development of hepatic insulin resistance and NASH by modifying FA composition. Recent studies have linked altered hepatic cholesterol homeostasis and cholesterol accumulation to the pathogenesis of NASH. In the present study, we further investigated the role of Elovl6 in the progression of Lithogenic Diet (LD)-induced steatohepatitis. We showed that the absence of Elovl6 suppresses hepatic lipid accumulation, plasma total cholesterol and total bile acid (BA) levels in LDL receptor-deficient (Ldlr−/−) mice challenged with a LD. The absence of Elovl6 also decreases hepatic inflammation, oxidative stress and liver injury, but increases the formation of cholesterol crystals in the less dilated gallbladder. These findings suggest that Elovl6-mediated changes in hepatic FA composition, especially oleic acid (C18:1n-9), control handling of hepatic cholesterol and BA, which protects against hepatotoxicity and steatohepatitis, but promotes gallstone formation in LD-fed Ldlr−/− mice.

Kirk J. Maurer - One of the best experts on this subject based on the ideXlab platform.

  • CCR2 and CD44 Promote Inflammatory Cell Recruitment during Fatty Liver Formation in a Lithogenic Diet Fed Mouse Model
    2016
    Co-Authors: Charlotte E. Egan, Erin K. Daugherity, Arlin B. Rogers, Eric Y. Denkers, Delbert Abi S. Abdallah, Kirk J. Maurer
    Abstract:

    Non-alcoholic fatty liver disease (NAFLD) is a common disease with a spectrum of presentations. The current study utilized a Lithogenic Diet model of NAFLD. The Diet was fed to mice that are either resistant (AKR) or susceptible (BALB/c and C57BL/6) to hepatitis followed by molecular and flow cytometric analysis. Following this, a similar approach was taken in congenic mice with specific mutations in immunological genes. The initial study identified a significant and profound increase in multiple ligands for the chemokine receptor CCR2 and an increase in CD44 expression in susceptible C57BL/6 (B6) but not resistant AKR mice. Ccr22/2 mice were completely protected from hepatitis and Cd442/2 mice were partially protected. Despite protection from inflammation, both strains displayed similar histological steatosis scores and significant increases in serum liver enzymes. CD45+CD44+ cells bound to hyaluronic acid (HA) in Diet fed B6 mice but not Cd442/2 or Ccr22/2 mice. Ccr22/2 mice displayed a diminished HA binding phenotype most notably in monocytes, and CD8+ T-cells. In conclusion, this study demonstrates that absence of CCR2 completely and CD44 partially reduces hepatic leukocyte recruitment. These data also provide evidence that there are multiple redundant CCR2 ligands produced during hepatic lipid accumulation and describes the induction of a strong HA binding phenotype in response to LD feeding in some subsets of leukocytes fro

  • CCR2 and CD44 Promote Inflammatory Cell Recruitment during Fatty Liver Formation in a Lithogenic Diet Fed Mouse Model
    PloS one, 2013
    Co-Authors: Charlotte E. Egan, Erin K. Daugherity, Arlin B. Rogers, Delbert S. Abi Abdallah, Eric Y. Denkers, Kirk J. Maurer
    Abstract:

    Non-alcoholic fatty liver disease (NAFLD) is a common disease with a spectrum of presentations. The current study utilized a Lithogenic Diet model of NAFLD. The Diet was fed to mice that are either resistant (AKR) or susceptible (BALB/c and C57BL/6) to hepatitis followed by molecular and flow cytometric analysis. Following this, a similar approach was taken in congenic mice with specific mutations in immunological genes. The initial study identified a significant and profound increase in multiple ligands for the chemokine receptor CCR2 and an increase in CD44 expression in susceptible C57BL/6 (B6) but not resistant AKR mice. Ccr2−/− mice were completely protected from hepatitis and Cd44−/− mice were partially protected. Despite protection from inflammation, both strains displayed similar histological steatosis scores and significant increases in serum liver enzymes. CD45+CD44+ cells bound to hyaluronic acid (HA) in Diet fed B6 mice but not Cd44−/− or Ccr2−/− mice. Ccr2−/− mice displayed a diminished HA binding phenotype most notably in monocytes, and CD8+ T-cells. In conclusion, this study demonstrates that absence of CCR2 completely and CD44 partially reduces hepatic leukocyte recruitment. These data also provide evidence that there are multiple redundant CCR2 ligands produced during hepatic lipid accumulation and describes the induction of a strong HA binding phenotype in response to LD feeding in some subsets of leukocytes from susceptible strains.

  • C57BL/6 mice are highly susceptible to Diet induced hepatitis.
    2013
    Co-Authors: Charlotte E. Egan, Erin K. Daugherity, Arlin B. Rogers, Eric Y. Denkers, Delbert Abi S. Abdallah, Kirk J. Maurer
    Abstract:

    (A) Liver leukocytes (CD45+ cells) were quantified in C57BL/6 (B6), BALB/c, and AKR mice fed either a standard Diet (SD) or 4 weeks of Lithogenic Diet (LD) (*P

  • Components of the biliary phenotype may be altered by crossfostering mice shortly after birth.
    2013
    Co-Authors: Jacqueline J. Fremont-rahl, Martin C. Carey, Carlos Umana, Mark T. Whary, Nancy S. Taylor, Sureshkumar Muthupalani, James G. Fox, Kirk J. Maurer
    Abstract:

    (A) Normalized gallbladder weight (B) mucin gel score (C) Liquid crystal phase separation (D) cholesterol monohydrate crystal formation, (E) sandy stone formation and (F) cholesterol gallstone formation were analyzed after 8 weeks of Lithogenic Diet feeding. (A) Both Tac and Jax fostered to Tac developed significantly larger gallbladders (*P

  • Biliary phenotype of genetically related BALB/cAnNTac (Tac) and BALB/cByJ (ByJ) and BALB/cJBomTac (Bom) and BALB/cJ (Jax) mice.
    2013
    Co-Authors: Jacqueline J. Fremont-rahl, Martin C. Carey, Carlos Umana, Mark T. Whary, Nancy S. Taylor, Sureshkumar Muthupalani, James G. Fox, Kirk J. Maurer
    Abstract:

    (A) Normalized gallbladder weight (B) mucin gel score (C) Liquid crystal phase separation (D) cholesterol monohydrate crystal formation, (E) sandy stone formation and (F) cholesterol gallstone formation were analyzed after 8 weeks of Lithogenic Diet feeding. (A) Normalized gallbladder weight significantly differed between Tac mice and both ByJ and Jackson mice (*P