scholarly journals The Potential of the FSP1cre-Pparb/d−/− Mouse Model for Studying Juvenile NAFLD

2019 ◽  
Vol 20 (20) ◽  
pp. 5115 ◽  
Author(s):  
Chen ◽  
Zhuang ◽  
Sng ◽  
Tan ◽  
Wahli
Keyword(s):  
Fatty Acid ◽  
Kupffer Cells ◽  
High Fat Diet ◽  
Macrophage Activation ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Qpcr Analysis ◽  
Alcoholic Fatty Liver Disease ◽  
Liver Cell Population

Non-alcoholic fatty liver disease (NAFLD) can progress from steatosis to non-alcoholic steatohepatitis (NASH) characterized by liver inflammation, possibly leading to cirrhosis and hepatocellular carcinoma (HCC). Mice with impaired macrophage activation, when fed a high-fat diet, develop severe NASH. Evidence is mounting that Kupffer cells are implicated. However, it is unknown whether the resident CD68+ or bone marrow-derived CD11b+ Kupffer cells are involved. Characterization of the FSP1cre-Pparb/d−/− mouse liver revealed that FSP1 is expressed in CD11b+ Kupffer cells. Although these cells only constitute a minute fraction of the liver cell population, Pparb/d deletion in these cells led to remarkable hepatic phenotypic changes. We report that a higher lipid content was present in postnatal day 2 (P2) FSP1cre-Pparb/d−/− livers, which diminished after weaning. Quantification of total lipids and triglycerides revealed that P2 and week 4 of age FSP1cre-Pparb/d−/− livers have higher levels of both. qPCR analysis also showed upregulation of genes involved in fatty acid β-oxidation, and fatty acid and triglyceride synthesis pathways. This result is further supported by western blot analysis of proteins in these pathways. Hence, we propose that FSP1cre-Pparb/d−/− mice, which accumulate lipids in their liver in early life, may represent a useful animal model to study juvenile NAFLD.

scholarly journals Lack of ClC-2 Alleviates High Fat Diet-Induced Insulin Resistance and Non-Alcoholic Fatty Liver Disease

2018 ◽  
Vol 45 (6) ◽  
pp. 2187-2198 ◽  
Author(s):  
Dongxia Fu ◽  
Haibin Cui ◽  
Yunna Zhang
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Lipid Accumulation ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Background/Aims: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. This study aims to investigate whether chloride channel 2 (ClC-2) is involved in high fat diet (HFD)-induced NAFLD and possible molecular mechanisms. Methods: ClC-2 expression was liver-specifically downregulated using adeno-associated virus in C57BL/6 mice treated with a chow diet or HFD for 12 weeks. Peripheral blood and liver tissues were collected for biochemical and pathological estimation respectively. Western blotting was applied to detect the protein expressions of lipid synthesis-related enzymes and the phosphorylated level of IRS-1, Akt and mTOR. Results: ClC-2 mRNA level was significantly increased in patients with non-alcoholic steatohepatitis, which positively correlated with the plasma levels of alanine transaminase (ALT), aspartate transaminase (AST) and insulin. Knockdown of ClC-2 in liver attenuated HFD-induced weight gain, obesity, hepatocellular ballooning, and liver lipid accumulation and fibrosis, accompanied by reduced plasma free fatty acid (FFA), triglyceride (TG), total cholesterol (TC), ALT, AST, glucose and insulin levels and homeostasis model of insulin resistance (HOMA-IR) value. Moreover, HFD-treated mice lacking ClC-2 showed inhibited hepatic lipid accumulation via regulating lipid metabolism through decreasing sterol regulatory element binding protein (SREBP)-1c expression and its downstream targeting enzymes such as fatty acid synthase (FAS), HMG-CoA reductase (HMGCR) and acetyl-Coenzyme A carboxylase (ACCα). In addition, in vivo and in vitro results demonstrated that ClC-2 downregulation in HFD-treated mice or HepG2 cells increased the sensitivity to insulin via activation of IRS-1/Akt/mTOR signaling pathway. Conclusion: Our present study reveals a critical role of ClC-2 in regulating metabolic diseases. Mice lacking ClC-2 are associated with a remarkably beneficial metabolic phenotype, suggesting that decreasing ClC-2 may be an attractive therapeutic strategy for the treatment of NAFLD.

scholarly journals Lonicera caerulea Extract Attenuates Non-Alcoholic Fatty Liver Disease in Free Fatty Acid-Induced HepG2 Hepatocytes and in High Fat Diet-Fed Mice

Nutrients ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 494 ◽  
Author(s):  
Miey Park ◽  
Jeong-Hyun Yoo ◽  
You-Suk Lee ◽  
Hae-Jeung Lee
Keyword(s):  
Fatty Acid ◽  
Lipid Accumulation ◽  
High Fat Diet ◽  
Hepg2 Cells ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Lonicera Caerulea ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Honeyberry (Lonicera caerulea) has been used for medicinal purposes for thousands of years. Its predominant anthocyanin, cyanidin-3-O-glucoside (C3G), possesses antioxidant and many other potent biological activities. We aimed to investigate the effects of honeyberry extract (HBE) supplementation on HepG2 cellular steatosis induced by free fatty acids (FFA) and in diet-induced obese mice. HepG2 cells were incubated with 1 mM FFA to induce lipid accumulation with or without HBE. Obesity in mice was induced by a 45% high fat diet (HFD) for 6 weeks and subsequent supplementation of 0.5% HBE (LH) and 1% HBE (MH) for 6 weeks. HBE suppressed fatty acid synthesis and ameliorated lipid accumulation in HepG2 cells induced by FFA. Moreover, HBE also decreased lipid accumulation in the liver in the supplemented HBE group (LH, 0.5% or MH, 1%) compared with the control group. The expressions of adipogenic genes involved in hepatic lipid metabolism of sterol regulatory element-binding protein-1 (SREBP-1c), CCAAT/enhancer-binding protein alpha (C/EBPα), peroxisome proliferator-activated receptor gamma (PPARγ), and fatty acid synthase (FAS) were decreased both in the HepG2 cells and in the livers of HBE-supplemented mice. In addition, HBE increased mRNA and protein levels of carnitine palmitoyltransferase (CPT-1) and peroxisome proliferator-activated receptor α (PPARα), which are involved in fatty acid oxidation. Furthermore, HBE treatment increased the phosphorylation of AMP-activated protein kinase (AMPK) and Acetyl CoA Carboxylase (ACC). Honeyberry effectively reduced triglyceride accumulation through down-regulation of hepatic lipid metabolic gene expression and up-regulation of the activation of AMPK and ACC signaling in both the HepG2 cells as well as in livers of diet-induced obese mice. These results suggest that HBE may actively ameliorate non-alcoholic fatty liver disease.

scholarly journals Holistic Characterization of Single Hepatocyte Transcriptome Responses to High Fat Diet

2020 ◽  
Author(s):  
Sung Rye Park ◽  
Chun-Seok Cho ◽  
Jingyue Xi ◽  
Hyun-Min Kang ◽  
Jun Hee Lee
Keyword(s):  
Single Cell ◽  
High Fat Diet ◽  
Marker Genes ◽  
Specific Marker ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Independent Effects ◽  
Parenchymal Cells ◽  
Alcoholic Fatty Liver Disease

During nutritional overload and obesity, hepatocyte function is grossly altered, and a subset of hepatocytes begins to accumulate fat droplets, leading to non-alcoholic fatty liver disease (NAFLD). Recent single cell studies revealed how non-parenchymal cells, such as macrophages, hepatic stellate cells, and endothelial cells, heterogeneously respond to NAFLD. However, it remains to be characterized how hepatocytes, the major constituents of the liver, respond to nutritional overload in NAFLD. Here, using droplet-based single cell RNA-sequencing (Drop-seq), we characterized how the transcriptomic landscape of individual hepatocytes is altered in response to high-fat diet (HFD) and NAFLD. We showed that entire hepatocytes population undergoes substantial transcriptome changes upon HFD, although the patterns of alteration were highly heterogeneous with zonation-dependent and -independent effects. Periportal (zone 1) hepatocytes downregulated many zone 1-specific marker genes, while a small number of genes mediating gluconeogenesis were upregulated. Pericentral (zone 3) hepatocytes also downregulated many zone 3-specific genes; however, they upregulated several genes that promote HFD-induced fat droplet formation, consistent with findings that zone 3 hepatocytes accumulate more lipid droplets. Zone 3 hepatocytes also upregulated ketogenic pathways as an adaptive mechanism to HFD. Interestingly, many of the top HFD-induced genes, which encode proteins regulating lipid metabolism, were strongly co-expressed with each other in a subset of hepatocytes, producing a variegated pattern of spatial co-localization that is independent of metabolic zonation. In conclusion, our dataset provides a useful resource for understanding hepatocellular alteration during NAFLD at single cell level.

scholarly journals Sodium fluorocitrate having inhibitory effect on fatty acid uptake ameliorates high fat diet-induced non-alcoholic fatty liver disease in C57BL/6J mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Seung A. Hong ◽  
Ik-Rak Jung ◽  
Sung-E. Choi ◽  
Yoonjung Hwang ◽  
Soo-Jin Lee ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Fatty Acid Uptake ◽  
Acid Uptake ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

AbstractNon-alcoholic fatty liver disease (NAFLD) is excessive fat build-up in the liver without alcohol consumption and includes hepatic inflammation and damage. Excessive influx of fatty acids to liver from circulation is thought to be a pathogenic cause for the development of NAFLD. Thus, inhibition of fatty acid intake into hepatocyte would be a maneuver for protection from high fat diet (HFD)-induced NAFLD. This study was initiated to determine whether sodium fluorocitrate (SFC) as a fatty acid uptake inhibitor could prevent palmitate-induced lipotoxicity in hepatocytes and protect the mice from HFD-induced NAFLD. SFC significantly inhibited the cellular uptake of palmitate in HepG2 hepatocytes, and thus prevented palmitate-induced fat accumulation and death in these cells. Single treatment with SFC reduced fasting-induced hepatic steatosis in C57BL/6J mice. Concurrent treatment with SFC for 15 weeks in HFD-fed C57BL/6J mice prevented HFD-induced fat accumulation and stress/inflammatory signal activation in the liver. SFC restored HFD-induced increased levels of serum alanine aminotransferase and aspartate aminotransferases as hepatic injury markers in these mice. SFC treatment also improved HFD-induced hepatic insulin resistance, and thus ameliorated HFD-induced hyperglycemia. In conclusion, inhibition of fatty acid mobilization into liver through SFC treatment can be a strategy to protect from HFD-induced NAFLD.

scholarly journals Holistic Characterization of Single Hepatocyte Transcriptome Responses to High Fat Diet

2020 ◽  
Author(s):  
Sung Rye Park ◽  
Chun-Seok Cho ◽  
Jingyue Xi ◽  
Hyun Min Kang ◽  
Jun Hee Lee
Keyword(s):  
Single Cell ◽  
High Fat Diet ◽  
Marker Genes ◽  
Specific Marker ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Independent Effects ◽  
Parenchymal Cells ◽  
Alcoholic Fatty Liver Disease

AbstractDuring nutritional overload and obesity, hepatocyte function is grossly altered, and a subset of hepatocytes begins to accumulate fat droplets, leading to non-alcoholic fatty liver disease (NAFLD). Recent single cell studies revealed how non-parenchymal cells, such as macrophages, hepatic stellate cells, and endothelial cells, heterogeneously respond to NAFLD. However, it remains to be characterized how hepatocytes, the major constituents of the liver, respond to nutritional overload in NAFLD. Here, using droplet-based single cell RNA-sequencing (Drop-seq), we characterized how the transcriptomic landscape of individual hepatocytes is altered in response to high-fat diet (HFD) and NAFLD. We showed that the entire hepatocytes population undergoes substantial transcriptome changes upon HFD, although the patterns of alteration were highly heterogeneous with zonation-dependent and –independent effects. Periportal (zone 1) hepatocytes downregulated many zone 1-specific marker genes, while a small number of genes mediating gluconeogenesis were upregulated. Pericentral (zone 3) hepatocytes also downregulated many zone 3-specific genes; however, they upregulated several genes that promote HFD-induced fat droplet formation, consistent with findings that zone 3 hepatocytes accumulate more lipid droplets. Zone 3 hepatocytes also upregulated ketogenic pathways as an adaptive mechanism to HFD. Interestingly, many of the top HFD-induced genes, which encode proteins regulating lipid metabolism, were strongly co-expressed with each other in a subset of hepatocytes, producing a variegated pattern of spatial co-localization that is independent of metabolic zonation. In conclusion, our dataset provides a useful resource for understanding hepatocellular alteration during NAFLD at single cell level.

scholarly journals Maternal tadalafil therapy for fetal growth restriction prevents non-alcoholic fatty liver disease and adipocyte hypertrophy in the offspring

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Takuya Kawamura ◽  
Hiroaki Tanaka ◽  
Ryota Tachibana ◽  
Kento Yoshikawa ◽  
Shintaro Maki ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fetal Growth ◽  
Fetal Programming ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Control Group ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

AbstractWe aimed to investigate the effects of maternal tadalafil therapy on fetal programming of metabolic function in a mouse model of fetal growth restriction (FGR). Pregnant C57BL6 mice were divided into the control, L-NG-nitroarginine methyl ester (L-NAME), and tadalafil + L-NAME groups. Six weeks after birth, the male pups in each group were given a high-fat diet. A glucose tolerance test (GTT) was performed at 15 weeks and the pups were euthanized at 20 weeks. We then assessed the histological changes in the liver and adipose tissue, and the adipocytokine production. We found that the non-alcoholic fatty liver disease activity score was higher in the L-NAME group than in the control group (p < 0.05). Although the M1 macrophage numbers were significantly higher in the L-NAME/high-fat diet group (p < 0.001), maternal tadalafil administration prevented this change. Moreover, the epididymal adipocyte size was significantly larger in the L-NAME group than in the control group. This was also improved by maternal tadalafil administration (p < 0.05). Further, we found that resistin levels were significantly lower in the L-NAME group compared to the control group (p < 0.05). The combination of exposure to maternal L-NAME and a high-fat diet induced glucose impairment and non-alcoholic fatty liver disease. However, maternal tadalafil administration prevented these complications. Thus, deleterious fetal programming caused by FGR might be modified by in utero intervention with tadalafil.

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