scholarly journals Integrated Transcriptomic and Translatomic Inquiry of the Role of Betaine on Lipid Metabolic Dysregulation Induced by a High-Fat Diet

2021 ◽  
Vol 8 ◽  
Author(s):  
Tengda Huang ◽  
Lin Yu ◽  
Hongyuan Pan ◽  
Zeqiang Ma ◽  
Tian Wu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
High Fat Diet ◽  
Liver Lipid ◽  
Liver Steatosis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Translational Efficiency ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Translational Level

An excessive high-fat/energy diet is a major cause of obesity and linked complications, such as non-alcoholic fatty liver disease (NAFLD). Betaine has been shown to effectively improve hepatic lipid metabolism. However, the mechanistic basis for this improvement is largely unknown. Herein, integration of mRNA sequencing and ribosome footprints profiling (Ribo-seq) was used to investigate the means by which betaine alleviates liver lipid metabolic disorders induced by a high-fat diet. For the transcriptome, gene set enrichment analysis demonstrated betaine to reduce liver steatosis by up-regulation of fatty acid beta oxidation, lipid oxidation, and fatty acid catabolic processes. For the translatome, 574 differentially expressed genes were identified, 17 of which were associated with the NAFLD pathway. By combined analysis of transcriptome and translatome, we found that betaine had the greater effect on NAFLD at the translational level. Further, betaine decreased translational efficiency (TE) for IDI1, CYP51A1, TM7SF2, and APOA4, which are related to lipid biosynthesis. In summary, this study demonstrated betaine alleviating lipid metabolic dysfunction at the translational level. The transcriptome and translatome data integration approach used herein provides for a new understanding of the means by which to treat NAFLD.

Transcriptome and translatome analyses reveal the regulatory role of betaine in high fat diet (HFD)-induced hepatic steatosis

2021 ◽  
Author(s):  
Tengda Huang ◽  
Jingsu Yu ◽  
Zupeng Luo ◽  
Lin Yu ◽  
Siqi Liu ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Translational Regulation ◽  
Mrna Translation ◽  
Lipid Lowering ◽  
Common Disease ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Lowering Effect ◽  
Lipid Lowering Effect ◽  
Translational Level

Abstract Non-alcoholic fatty liver disease (NAFLD) is a common disease with a multitude of complications. Increasing evidence shows that the dietary supplement with betaine, a natural chemical molecule, can effectively reduce the fat accumulation in the liver. Translational regulation is considered to play a vital role in gene expression, but whether betaine functions through the regulation of gene translational level is still unclear. To this end, RNC-seq (ribosome-nascent chain complex bound mRNA sequencing) and RNA-seq co-analyses were performed to identify betaine target genes by using the liver samples from high-fat diet + betaine treated and high-fat diet treated mice. The results showed that betaine does play a lipid-lowering role by regulating the expression of gene translation levels; some NAFLD- and lipid metabolism- associated genes were differentially expressed at translational level, for example. And the mRNA translation ratio (TR) of gene significantly increased after betaine treatment. Besides, it is found that the regulation of some genes at transcriptional level is opposite to that at translational level, which indicates that transcriptional regulation and translational regulation may be independent from each other. Finally, we identified several candidate genes, especially Gpc1 , which may mediate the lipid-lowering effect of betaine in the liver. To sum up, this study depicted the molecular portrait of mice liver with or without betaine treatment from the angel of translatome and transcriptome, giving insights into the molecular mechanism of betaine-mediated lipid-lowering effect and also providing new clues for understanding and prevention of NAFLD.

scholarly journals OMEGA-3 FATTY ACID IMPROVE NON ALCOHOLIC FATTY LIVER INDUCED BY HIGH FAT DIET IN RATS.

2017 ◽  
Vol 5 (3) ◽  
pp. 505-512
Author(s):  
ReemM. Hashem ◽  
◽  
LailaA. Rashed ◽  
GhadaM. Safwat ◽  
IbrahimT. Ibrahim. ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Liver ◽  
High Fat Diet ◽  
Omega 3 ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Omega 3 Fatty Acid

scholarly journals P2Y2R Deficiency Ameliorates Hepatic Steatosis by Reducing Lipogenesis and Enhancing Fatty Acid β-Oxidation through AMPK and PGC-1α Induction in High-Fat Diet-Fed Mice

2021 ◽  
Vol 22 (11) ◽  
pp. 5528
Author(s):  
Theodomir Dusabimana ◽  
Eun Jung Park ◽  
Jihyun Je ◽  
Kyuho Jeong ◽  
Seung Pil Yun ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Liver Disease ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Purinergic Receptor ◽  
Lipolytic Enzyme ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Mitochondrial Fatty Acid

Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic liver disease associated with obesity and insulin resistance. Activation of the purinergic receptor P2Y2R has been reported to promote adipogenesis, inflammation and dyslipidemia in adipose tissues in obese mice. However, the role of P2Y2R and its mechanisms in NAFLD remain unknown. We hypothesized that P2Y2R deficiency may play a protective role in NAFLD by modulating lipid metabolism in the liver. In this study, we fed wild type and P2Y2R knockout mice with a high-fat diet (HFD) for 12 weeks and analyzed metabolic phenotypes. First, P2Y2R deficiency effectively improved insulin resistance with a reduction in body weight and plasma insulin. Second, P2Y2R deficiency attenuated hepatic lipid accumulation and injury with reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Third, P2Y2R deficiency decreased the expression of fatty acid synthesis mediators (cluster of differentiation (CD36), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1)); and increased the expression of adipose triglyceride lipase (ATGL), a lipolytic enzyme. Mechanistically, P2Y2R deficiency increased the AMP-activated protein kinase (AMPK) activity to improve mitochondrial fatty acid β-oxidation (FAO) by regulating acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase 1A (CPT1A)-mediated FAO pathway. In addition, P2Y2R deficiency increased peroxisome proliferator-activated gamma co-activator-1α (PGC-1α)-mediated mitochondrial biogenesis. Conclusively, P2Y2R deficiency ameliorated HFD-induced hepatic steatosis by enhancing FAO through AMPK signaling and PGC-1α pathway, suggesting P2Y2R as a promising therapeutic target for NAFLD.

scholarly journals Modulating hepatocarcinogenesis by porto-systemic vein shunting in a high-fat diet mouse model

2021 ◽  
Vol 108 (Supplement_4) ◽  
Author(s):  
A Peloso ◽  
Q Gex ◽  
M Tihy ◽  
B Moeckli ◽  
F Slits ◽  
...  
Keyword(s):  
Mouse Model ◽  
Growth Pattern ◽  
High Fat Diet ◽  
Tumor Volume ◽  
Portal Pressure ◽  
Liver Steatosis ◽  
Common Disease ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Systemic Vein

Abstract Objective Non-alcoholic fatty liver disease (NAFLD) is an increasingly common disease, which can lead to hepatocellular carcinoma (HCC). It is associated with an increased portal pressure, which can alter the intestinal barrier, increase the translocation of bacterial products, and further worsen NAFLD. We hypothesized that this vicious circle can be broken by surgical porto-systemic vein shunting (PSVS), and previously demonstrated that PSVS can decrease the histological features of NAFLD in a high-fat diet (HFD) mouse model. We now test whether PSVS can also impact de-novo hepatocarcinogenesis. Methods C57BL/6 mice received HFD starting from 4 weeks of age. HCC was induced by intraperitoneal injection of DEN at 25mg/kg on week 2 and PSVS (n = 18) (or sham surgery (n = 18)) are created at 8 weeks. HCC burden was assessed by MRI and, finally, by macroscopic and histomorphology assessments. HCC features of aggressiveness, including solid growth pattern and fat component have been also evaluated. Results At 40 weeks of HFD feeding, tumors were identified in all the animals. Shunted HFD mice showed a reduced number of tumor nodules compared to sham (median nodules 8 vs 14, -42.9%; p = 0.0471) while associated to a greater average total tumor volume (709.3 vs 197 mm3, +258,6%; p = 0.0245). This correlated with an increased median tumor volume in shunted mice (16.30 vs 72.45 mm3, +344,5%; p = 0.0011). Notably, HCC histology of shunted mice was hallmarked by accentuated trend concerning HCC fatty change combined to a less pronounced solid growth pattern (p = 0.193). Conclusion PSVS leads to the presence of larger HCCs, potentially linked to the proportionally increased arterial supply of the liver. However, it demonstrates a protective effect on HCC carcinogenesis (< number of tumors). Collectively, this data suggests that portal pressure could represent a potential therapeutic target to attenuate liver steatosis and NAFLD-related HCC carcinogenesis.

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 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 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.

High-fat diet induces mouse liver steatosis with a concomitant decline in energy metabolism: attenuation by eicosapentaenoic acid (EPA) or hydroxytyrosol (HT) supplementation and the additive effects upon EPA and HT co-administration

2019 ◽  
Vol 10 (9) ◽  
pp. 6170-6183 ◽  
Author(s):  
Francisca Echeverría ◽  
Rodrigo Valenzuela ◽  
Andrés Bustamante ◽  
Daniela Álvarez ◽  
Macarena Ortiz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Energy Metabolism ◽  
High Fat Diet ◽  
Mouse Liver ◽  
Liver Steatosis ◽  
Chain Polyunsaturated Fatty Acid ◽  
Additive Effects ◽  
High Fat ◽  
Long Chain

High-fat-diet (HFD) feeding is associated with liver oxidative stress (OS), n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) depletion, hepatic steatosis and mitochondrial dysfunction.

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