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

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.

scholarly journals Hepatic HuR protects against the pathogenesis of non-alcoholic fatty liver disease by targeting PTEN

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Mi Tian ◽  
Jingjing Wang ◽  
Shangming Liu ◽  
Xinyun Li ◽  
Jingyuan Li ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Hepatic Steatosis ◽  
Chow Diet ◽  
Alcoholic Fatty Liver ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pten Mrna ◽  
Normal Chow ◽  
Mice Liver

AbstractThe liver plays an important role in lipid and glucose metabolism. Here, we show the role of human antigen R (HuR), an RNA regulator protein, in hepatocyte steatosis and glucose metabolism. We investigated the level of HuR in the liver of mice fed a normal chow diet (NCD) and a high-fat diet (HFD). HuR was downregulated in the livers of HFD-fed mice. Liver-specific HuR knockout (HuRLKO) mice showed exacerbated HFD-induced hepatic steatosis along with enhanced glucose tolerance as compared with control mice. Mechanistically, HuR could bind to the adenylate uridylate-rich elements of phosphatase and tensin homolog deleted on the chromosome 10 (PTEN) mRNA 3′ untranslated region, resulting in the increased stability of Pten mRNA; genetic knockdown of HuR decreased the expression of PTEN. Finally, lentiviral overexpression of PTEN alleviated the development of hepatic steatosis in HuRLKO mice in vivo. Overall, HuR regulates lipid and glucose metabolism by targeting PTEN.

scholarly journals Hepatic HuR protects against the pathogenesis of non-alcoholic fatty liver disease

2020 ◽  
Author(s):  
Mi Tian ◽  
Xinyun Li ◽  
Jingyuan Li ◽  
Jianmin Yang ◽  
Cheng Zhang ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Chow Diet ◽  
Alcoholic Fatty Liver ◽  
Over Expression ◽  
Regulator Protein ◽  
Normal Chow ◽  
Alcoholic Fatty Liver Disease

Abstract Background: Liver plays an important role in lipid and glucose metabolism. Human antigen R (HuR) as an RNA regulator protein participates in many disease processes. Here, we investigated the specific role of HuR in hepatic steatosis and glucose metabolism.Methods: We investigated the level of HuR in liver from mice fed a normal chow diet (NCD) and high fat diet (HFD). Liver specific HuR knockout (HuRLKO) mice were generated and challenged with an HFD. Lipid levels and glucose metabolism index were examined. Results: HuR was downregulated in livers of HFD-fed mice. HuRLKO mice showed exacerbated HFD-induced hepatic steatosis but improved glucose tolerance as compared with controls. Consistently, HuR inhibited lipid accumulation in hepatocytes. Mechanically, HuR could bind to the mRNA of phosphatase and tensin homology deleted on chromosome 10 (PTEN), thus increasing their stability and translation. Finally, PTEN over-expression alleviated HFD-induced hepatic steatosis in HuRLKO mice.Conclusion: HuR modulates lipid and glucose metabolism through regulating PTEN expression.

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

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243497
Author(s):  
Cho-Rong Bae ◽  
Haiying Zhang ◽  
Young-Guen Kwon
Keyword(s):  
Amino Acid ◽  
Endothelial Dysfunction ◽  
Mouse Model ◽  
Hepatic Steatosis ◽  
Hepatic Fibrosis ◽  
Liver Sinusoidal Endothelial Cell ◽  
Alcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Alcoholic Steatohepatitis ◽  
Expression Of Genes

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.

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

PPAR Research ◽  
2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
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.

scholarly journals Loss of CTRP5 improves insulin action and hepatic steatosis

2016 ◽  
Vol 310 (11) ◽  
pp. E1036-E1052 ◽  
Author(s):  
Xia Lei ◽  
Susana Rodriguez ◽  
Pia S. Petersen ◽  
Marcus M. Seldin ◽  
Caitlyn E. Bowman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Insulin Action ◽  
Subcutaneous Fat ◽  
Physiological Role ◽  
Negative Regulator ◽  
Chow Diet ◽  
High Fat ◽  
Peripheral Tissues ◽  
Obesity And Diabetes

The gene that encodes C1q/TNF-related protein 5 (CTRP5), a secreted protein of the C1q family, is mutated in individuals with late-onset retinal degeneration. CTRP5 is widely expressed outside the eye and also circulates in plasma. Its physiological role in peripheral tissues, however, has yet to be elucidated. Here, we show that Ctrp5 expression is modulated by fasting and refeeding, and by different diets, in mice. Adipose expression of CTRP5 was markedly upregulated in obese and diabetic humans and in genetic and dietary models of obesity in rodents. Furthermore, human CTRP5 expression in the subcutaneous fat depot positively correlated with BMI. A genetic loss-of-function mouse model was used to address the metabolic function of CTRP5 in vivo. On a standard chow diet, CTRP5-deficient mice had reduced fasting insulin but were otherwise comparable with wild-type littermate controls in body weight and adiposity. However, when fed a high-fat diet, CTRP5-deficient animals had attenuated hepatic steatosis and improved insulin action. Loss of CTRP5 also improved the capacity of chow-fed aged mice to respond to subsequent high-fat feeding, as evidenced by decreased insulin resistance. In cultured adipocytes and myotubes, recombinant CTRP5 treatment attenuated insulin-stimulated Akt phosphorylation. Our results provide the first genetic and physiological evidence for CTRP5 as a negative regulator of glucose metabolism and insulin sensitivity. Inhibition of CTRP5 action may result in the alleviation of insulin resistance associated with obesity and diabetes.

Association between hepatic steatosis and hepatic expression of genes involved in innate immunity in patients with chronic hepatitis C

Cytokine ◽  
2013 ◽  
Vol 63 (2) ◽  
pp. 145-150 ◽  
Author(s):  
Hidenori Toyoda ◽  
Takashi Kumada ◽  
Seiki Kiriyama ◽  
Makoto Tanikawa ◽  
Yasuhiro Hisanaga ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Chronic Hepatitis ◽  
Hepatitis C ◽  
Hepatic Steatosis ◽  
Chronic Hepatitis C ◽  
Hepatic Expression ◽  
Expression Of Genes

scholarly journals Green Plant Pigment, Chlorophyllin, Ameliorates Non-alcoholic Fatty Liver Diseases (NAFLDs) Through Modulating Gut Microbiome in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
You Yang ◽  
Xile Jiang ◽  
Stephen J. Pandol ◽  
Yuan-Ping Han ◽  
Xiaofeng Zheng
Keyword(s):  
Insulin Resistance ◽  
Gut Microbiota ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Systemic Inflammation ◽  
Gut Microbiome ◽  
Liver Diseases ◽  
High Fat ◽  
Green Pigment ◽  
Alcoholic Fatty Liver

Non-alcoholic fatty liver diseases (NAFLDs) along with metabolic syndrome and Type-2 diabetes (T2D) are increasingly prevalent worldwide. Without an effective resolution, simple hepatic steatosis may lead to non-alcoholic steatohepatitis (NASH), characterized by hepatocyte damage, chronic inflammation, necrosis, fatty degeneration, and cirrhosis. The gut microbiome is vital for metabolic homeostasis. Conversely, dysbiosis contributes to metabolic diseases including NAFLD. Specifically, diet composition is critical for the enterotype of gut microbiota. We reasoned that green pigment rich in vegetables may modulate the gut microbiome for metabolic homeostasis. In this study, C57BL/6 mice under a high fat diet (HFD) were treated with sodium copper chlorophyllin (CHL), a water-soluble derivative of chlorophyll, in drinking water. After 28 weeks of HFD feeding, liver steatosis was established accompanied by gut microbiota dysbiosis, intestinal impairment, endotoxemia, systemic inflammation, and insulin resistance. Administration of CHL effectively alleviated systemic and intestinal inflammation and maintained tight junction in the intestinal barrier. CHL rebalanced gut microbiota in the mice under high fat feeding and attenuated hepatic steatosis, insulin resistance, dyslipidemia, and reduced body weight. Fecal flora transplants from the CHL-treated mice ameliorated steatosis as well. Thus, dietary green pigment or the administration of CHL may maintain gut eubiosis and intestinal integrity to attenuate systemic inflammation and relieve NASH.

scholarly journals Sarcopoterium spinosum Inhibited the Development of Non-Alcoholic Steatosis and Steatohepatitis in Mice

Nutrients ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 3044 ◽  
Author(s):  
Ayala Wollman ◽  
Tehila Daniel ◽  
Tovit Rosenzweig
Keyword(s):  
Liver Disease ◽  
Insulin Sensitivity ◽  
Hepatic Steatosis ◽  
Dependent Manner ◽  
Alcoholic Fatty Liver ◽  
Reduced Body ◽  
Expression Of Genes ◽  
Intimate Link ◽  
Sarcopoterium Spinosum

Non-alcoholic fatty liver disease (NAFLD) is a comorbidity of obesity, which gradually develops from hepatic steatosis into steatohepatitis (NASH) and eventually even into fibrosis or hepatic carcinoma. To date, there has been no specific and effective treatment for NAFLD. Sarcopoterium spinosum extract (SSE) was found to improve insulin sensitivity. Recognizing the intimate link between insulin resistance and NAFLD, the aim of this study was to investigate the effectivity of SSE in the prevention and management of NAFLD at various severities. SSE was given to high-fat diet (HFD)-fed mice (steatosis model) or to mice given a Western diet (WD) in the short or long term (NASH prevention or treatment, respectively). SSE reduced body weight accumulation, improved glucose tolerance and insulin sensitivity and prevented the development of hepatic steatosis. SSE also blocked the progression of liver disease toward NASH in a dose-dependent manner. The expression of genes involved in lipid metabolism, inflammation, and antioxidant machinery was regulated by SSE in both models of steatosis and NASH development. However, SSE failed to reverse the hepatic damage in the advanced model of NASH. In summary, SSE might be considered as a botanical supplement for the prevention and treatment of hepatic steatosis, and for slowing the deterioration toward NASH.

scholarly journals Maternal exercise conveys protection against NAFLD in the offspring via hepatic metabolic programming

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Inga Bae-Gartz ◽  
Philipp Kasper ◽  
Nora Großmann ◽  
Saida Breuer ◽  
Ruth Janoschek ◽  
...  
Keyword(s):  
Early Life ◽  
Body Weight Gain ◽  
Hepatic Metabolism ◽  
Underlying Mechanism ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Maternal Exercise

Abstract Maternal exercise (ME) during pregnancy has been shown to improve metabolic health in offspring and confers protection against the development of non-alcoholic fatty liver disease (NAFLD). However, its underlying mechanism are still poorly understood, and it remains unclear whether protective effects on hepatic metabolism are already seen in the offspring early life. This study aimed at determining the effects of ME during pregnancy on offspring body composition and development of NAFLD while focusing on proteomic-based analysis of the hepatic energy metabolism during developmental organ programming in early life. Under an obesogenic high-fat diet (HFD), male offspring of exercised C57BL/6J-mouse dams were protected from body weight gain and NAFLD in adulthood (postnatal day (P) 112). This was associated with a significant activation of hepatic AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor alpha (PPARα) and PPAR coactivator-1 alpha (PGC1α) signaling with reduced hepatic lipogenesis and increased hepatic β-oxidation at organ programming peak in early life (P21). Concomitant proteomic analysis revealed a characteristic hepatic expression pattern in offspring as a result of ME with the most prominent impact on Cholesterol 7 alpha-hydroxylase (CYP7A1). Thus, ME may offer protection against offspring HFD-induced NAFLD by shaping hepatic proteomics signature and metabolism in early life. The results highlight the potential of exercise during pregnancy for preventing the early origins of NAFLD.

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