The endothelial dysfunction blocker CU06-1004 ameliorates choline-deficient L-amino acid diet-induced non-alcoholic steatohepatitis in mice

Non-alcoholic steatohepatitis (NASH) is a severe, advanced form of non-alcoholic fatty liver disease (NAFLD) that is associated with features of metabolic syndrome and characterized by hepatic steatosis, inflammation, and fibrosis. In addition, NASH is associated with endothelial dysfunction within the hepatic vasculature. Treatment with CU06-1004 (previously called Sac-1004) ameliorates endothelial dysfunction by inhibiting hyperpermeability and inflammation. In this study, we investigated the protective effects of CU06-1004 in a choline-deficient L-amino acid (CDAA)-induced mouse model of NASH for 3 or 6 weeks. Specifically, we evaluated the effects of CU06-1004 on lipid accumulation, inflammation, hepatic fibrosis, and liver sinusoidal endothelial cell (LSEC) capillarization through biochemical analysis, immunohistochemistry, and real-time PCR. We found that the administration of CU06-1004 to mice improved liver triglyceride (TG) and serum alanine aminotransferase (ALT) in this CDAA-induced model of NASH for 6 weeks. In groups of NASH induced mice for both 3 and 6 weeks, CU06-1004 significantly reduced the hepatic expression of genes related to lipogenesis, inflammation, and cell adhesion. However, expression of genes related to hepatic fibrosis and vascular endothelial changes were only decreased in animals with mild NASH. These results suggest that the administration of CU06-1004 suppresses hepatic steatosis, inflammation, fibrosis, and LSEC capillarization in a CDAA-induced mouse model of NASH. This suggests that CU06-1004 has therapeutic potential for the treatment of mild NASH.

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Role of Mcpip1 in obesity-induced hepatic steatosis as determined by myeloid and liver-specific conditional knockouts

10.1101/2020.09.17.301531 ◽

2020 ◽

Author(s):

Natalia Pydyn ◽

Dariusz Żurawek ◽

Joanna Kozieł ◽

Edyta Kuś ◽

Kamila Wojnar-Lason ◽

...

Keyword(s):

Glucose Metabolism ◽

Hepatic Steatosis ◽

Systemic Inflammation ◽

Hepatic Metabolism ◽

Negative Regulator ◽

Chow Diet ◽

Alcoholic Fatty Liver ◽

Hepatic Expression ◽

Expression Of Genes ◽

Myeloid Leukocytes

AbstractMonocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase1) is a negative regulator of inflammation, acting through cleavage of transcripts coding for proinflammatory cytokines and by inhibition of NFκB activity. Moreover, it was demonstrated, that MCPIP1 regulates lipid metabolism both in adipose tissue and hepatocytes. In this study, we investigated the effects of tissue-specific Mcpip1 deletion on the regulation of hepatic metabolism and development of non-alcoholic fatty liver disease (NAFLD).We used knock-in control Mcpip1fl/fl mice and animals with deletion of Mcpip1 in myeloid leukocytes (Mcpip1fl/flLysMCre) and in hepatocytes (Mcpip1fl/flAlbCre), which were fed chow or a high-fat diet (HFD) for 12 weeks. Mcpip1fl/flLysMCre mice were fed a chow diet were characterized by a significantly reduced hepatic expression of genes regulating lipid and glucose metabolism, which subsequently resulted in hypoglycemia and dyslipidemia. These animals also displayed systemic inflammation, demonstrated by increased concentrations of cytokines in the plasma. On the other hand, there were no significant changes in phenotype in Mcpip1fl/flAlbCre mice. Although we detected a reduced hepatic expression of genes regulating glucose metabolism and β-oxidation in these mice, they remained asymptomatic. Upon feeding them a HFD, Mcpip1fl/flLysMCre mice did not develop obesity, glucose intolerance, nor hepatic steatosis, but were characterized by hypoglycemia and dyslipidemia, along with proinflammatory phenotype with symptoms of cachexia. Mcpip1fl/flAlbCre animals, following a HFD, became hypercholesterolemic, but accumulated lipids in the liver at the same level as Mcpip1fl/fl mice, and no changes in the level of soluble factors tested in the plasma were detected.In conclusion, we have demonstrated that Mcpip1 protein plays an important role in the liver homeostasis. Depletion of Mcpip1 in myeloid leukocytes, followed by systemic inflammation, has a more pronounced effect on controlling liver metabolism and homeostasis than the depletion of Mcpip1 in hepatocytes.

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Dose threshold for radiation induced fetal programming in a mouse model at 4 months of age: Hepatic expression of genes and proteins involved in glucose metabolism and glucose uptake in brown adipose tissue

PLoS ONE ◽

10.1371/journal.pone.0231650 ◽

2020 ◽

Vol 15 (4) ◽

pp. e0231650

Author(s):

Caitlund Q. Davidson ◽

Sujeenthar Tharmalingam ◽

Sarah Niccoli ◽

Ashley Nemec-Bakk ◽

Sandhya Khurana ◽

...

Keyword(s):

Adipose Tissue ◽

Glucose Metabolism ◽

Mouse Model ◽

Brown Adipose Tissue ◽

Fetal Programming ◽

Dose Threshold ◽

Hepatic Expression ◽

Expression Of Genes ◽

Brown Adipose ◽

Radiation Induced

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Aberrant Hepatic Expression of PPARγ2 Stimulates Hepatic Lipogenesis in a Mouse Model of Obesity, Insulin Resistance, Dyslipidemia, and Hepatic Steatosis

Journal of Biological Chemistry ◽

10.1074/jbc.m604709200 ◽

2006 ◽

Vol 281 (49) ◽

pp. 37603-37615 ◽

Cited By ~ 108

Author(s):

Yuan-Li Zhang ◽

Antonio Hernandez-Ono ◽

Patty Siri ◽

Stuart Weisberg ◽

Donna Conlon ◽

...

Keyword(s):

Insulin Resistance ◽

Mouse Model ◽

Hepatic Steatosis ◽

Hepatic Lipogenesis ◽

Hepatic Expression

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Treatment with Lobeglitazone Attenuates Hepatic Steatosis in Diet-Induced Obese Mice

PPAR Research ◽

10.1155/2018/4292509 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Sorim Choung ◽

Kyong Hye Joung ◽

Bo Ram You ◽

Sang Ki Park ◽

Hyun Jin Kim ◽

...

Keyword(s):

Insulin Resistance ◽

Hepatic Steatosis ◽

Plasma Cholesterol ◽

Cholesterol Biosynthesis ◽

Peroxisome Proliferator ◽

Obese Mice ◽

Nonalcoholic Fatty Liver ◽

Hepatic Lipid ◽

Hepatic Expression ◽

Expression Of Genes

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance. The peroxisome proliferator-activated receptor (PPAR) activators, thiazolidinediones, (TZDs), are insulin sensitizers used as a treatment for NAFLD. However, TZDs are a controversial treatment for NAFLD because of conflicting results regarding hepatic steatosis and fibrosis. To evaluate a possible effective drug for treatment of NAFLD, we investigated the effects of a newly developed TZD, lobeglitazone, with an emphasis on hepatic lipid metabolism. Lobeglitazone treatment for 4 weeks in high fat diet- (HFD-) induced obese mice (HL group) improved insulin resistance and glucose intolerance compared to HFD-induced obese mice (HU group). The gene levels related to hepatic gluconeogenesis also decreased after treatment by lobeglitazone. The livers of mice in the HL group showed histologically reduced lipid accumulation, with lowered total plasma cholesterol and triglyceride levels. In addition, the HL group significantly decreased the hepatic expression of genes associated with lipid synthesis, cholesterol biosynthesis, and lipid droplet development and increased the hepatic expression of genes associated with fatty acid β-oxidation, thus suggesting that lobeglitazone decreased hepatic steatosis and reversed hepatic lipid dysregulation. Livers with steatohepatitis contained increased levels of PPARγ and phosphorylated PPARγ at serine 273, leading to downregulation of expression of genes associated with insulin sensitivity. Notably, the treatment of lobeglitazone increased the protein levels of PPARα and diminished levels of PPARγ phosphorylated at serine 273, which were increased by a HFD, suggesting that induction of PPARα and posttranslational modification of PPARγ in livers by lobeglitazone might be an underlying mechanism of the improvement seen in NAFLD. Taken together, our data showed that lobeglitazone might be an effective treatment for NAFLD.

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Use of GP73 in the diagnosis of non-alcoholic steatohepatitis and the staging of hepatic fibrosis

Journal of International Medical Research ◽

10.1177/03000605211055378 ◽

2021 ◽

Vol 49 (11) ◽

pp. 030006052110553

Author(s):

Yadi Li ◽

Yan Yang ◽

Yufang Li ◽

Ping Zhang ◽

Gaiying Ge ◽

...

Keyword(s):

Hepatic Fibrosis ◽

High Serum ◽

Gamma Glutamyl Transferase ◽

Strong Positive Correlation ◽

Characteristic Analysis ◽

Alcoholic Fatty Liver ◽

Alcoholic Steatohepatitis ◽

Golgi Protein ◽

Glutamyl Transferase ◽

Nafld Activity Score

Objective To evaluate the utility of Golgi protein 73 (GP73) in the diagnosis of non-alcoholic steatohepatitis (NASH) and hepatic fibrosis (HF) staging. Methods Ninety-one patients with non-alcoholic fatty liver disease (NAFLD) were allocated to NAFL (n = 46) and NASH (n = 45) groups according to their NAFLD activity score (NAS), and there were 30 healthy controls. Serum GP73 was measured by ELISA, GP73 protein expression was evaluated using immunohistochemistry, and FibroScan was used to determine liver hardness. Results The serum GP73 concentrations of the NAFL and NASH groups were significantly higher than those of controls. GP73 expression in the liver of the patients gradually progressed from absent or low to moderate or high. Serum GP73 positively correlated with liver expression, and the serum and liver GP73 of the patients positively correlated with FibroScan value and HF stage. There was a strong positive correlation of the combination of alanine aminotransferase, gamma glutamyl transferase and GP73 with NASH. The combination of serum GP73 and FibroScan value was found to predict NASH (NAS > 4) and advanced HF (stage ≥2) in patients with NAFLD using receiver operating characteristic analysis. Conclusion Serum GP73 may be useful in the diagnosis of NASH and the staging of HF.

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