scholarly journals ERK-dependent mTOR pathway is involved in berberine-induced autophagy in hepatic steatosis

2016 ◽  
Vol 57 (4) ◽  
pp. 251-260 ◽  
Author(s):  
Qin He ◽  
Dan Mei ◽  
Sha Sha ◽  
Shanshan Fan ◽  
Lin Wang ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Mtor Pathway ◽  
Mice Model ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Positive Effects

Non-alcoholic fatty liver disease (NAFLD) is a burgeoning health problem and is considered as a hepatic manifestation of metabolic syndrome. Increasing evidence demonstrates that berberine (BBR), a natural plant alkaloid, is beneficial for obesity-associated NAFLD. However, the mechanisms about how BBR improves hepatic steatosis remain uncertain. Recently, some reports revealed that enhanced autophagy could decrease hepatic lipid accumulation. In this study, we first established a high-fed diet (HFD) mice model and oleate–palmitate-induced lipotoxicity hepatocytes to explore the association among BBR, autophagy and hepatic steatosis. Our data demonstrated that BBR had profound effects on improving hepatic lipid accumulation bothin vivoandin vitro, and led to high autophagy flux. The molecular alterations proceeding these changes were characterized by inhibition of the ERK/mTOR pathway. These findings suggest an important mechanism for the positive effects of BBR on hepatic steatosis, and may provide new evidence for the clinical use of BBR in NAFLD.

scholarly journals Dapagliflozin Alleviates Hepatic Steatosis by Restoring Autophagy via the AMPK-mTOR Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Liuran Li ◽  
Qinghua Li ◽  
Wenbin Huang ◽  
Yibing Han ◽  
Huiting Tan ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Mtor Pathway ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Zdf Rats ◽  
Oxidation Enzyme

As a newly approved oral hypoglycaemic agent, the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin, which is derived from the natural product phlorizin can effectively reduce blood glucose. Recent clinical studies have found that dapagliflozin alleviates non-alcoholic fatty liver disease (NAFLD), but the specific mechanism remains to be explored. This study aimed to investigate the underlying mechanism of dapagliflozin in alleviating hepatocyte steatosis in vitro and in vivo. We fed the spontaneous type 2 diabetes mellitus rats with high-fat diets and cultured human normal liver LO2 cells and human hepatocellular carcinoma HepG2 cells with palmitic acid (PA) to induce hepatocellular steatosis. Dapagliflozin attenuated hepatic lipid accumulation both in vitro and in vivo. In Zucker diabetic fatty (ZDF) rats, dapagliflozin reduced hepatic lipid accumulation via promoting phosphorylation of acetyl-CoA carboxylase 1 (ACC1), and upregulating lipid β-oxidation enzyme acyl-CoA oxidase 1 (ACOX1). Furthermore, dapagliflozin increased the expression of the autophagy-related markers LC3B and Beclin1, in parallel with a drop in p62 level. Similar effects were observed in PA-stimulated LO2 cells and HepG2 cells. Dapagliflozin treatment could also significantly activated AMPK and reduced the phosphorylation of mTOR in ZDF rats and PA-stimulated LO2 cells and HepG2 cells. We demonstrated that dapagliflozin ameliorates hepatic steatosis by decreasing lipogenic enzyme, while inducing fatty acid oxidation enzyme and autophagy, which could be associated with AMPK activation. Moreover, our results indicate that dapagliflozin induces autophagy via the AMPK-mTOR pathway. These findings reveal a novel clinical application and functional mechanism of dapagliflozin in the treatment of NAFLD.

scholarly journals Liraglutide Alleviates Hepatic Steatosis by Activating the TFEB-Regulated Autophagy-Lysosomal Pathway

2020 ◽  
Vol 8 ◽  
Author(s):  
Yunyun Fang ◽  
Linlin Ji ◽  
Chaoyu Zhu ◽  
Yuanyuan Xiao ◽  
Jingjing Zhang ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Underlying Mechanism ◽  
Autophagic Flux ◽  
Alcoholic Fatty Liver ◽  
Lipid Degradation ◽  
Hepatic Lipid Accumulation ◽  
Lysosome Biogenesis

Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has been demonstrated to alleviate non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism has not been fully elucidated. Increasing evidence suggests that autophagy is involved in the pathogenesis of hepatic steatosis. In this study, we examined whether liraglutide could alleviate hepatic steatosis through autophagy-dependent lipid degradation and investigated the underlying mechanisms. Herein, the effects of liraglutide on NAFLD were evaluated in a high-fat diet (HFD)-induced mouse model of NAFLD as well as in mouse primary and HepG2 hepatocytes exposed to palmitic acid (PA). The expression of the GLP-1 receptor (GLP-1R) was measured in vivo and in vitro. Oil red O staining was performed to detect lipid accumulation in hepatocytes. Electron microscopy was used to observe the morphology of autophagic vesicles and autolysosomes. Autophagic flux activity was measured by infecting HepG2 cells with mRFP-GFP-LC3 adenovirus. The roles of GLP-1R and transcription factor EB (TFEB) in autophagy-lysosomal activation were explored using small interfering RNA. Liraglutide treatment alleviated hepatic steatosis in vivo and in vitro. In models of hepatic steatosis, microtubule-associated protein 1B light chain-3-II (LC3-II) and SQSTM1/P62 levels were elevated in parallel to blockade of autophagic flux. Liraglutide treatment restored autophagic activity by improving lysosomal function. Furthermore, treatment with autophagy inhibitor chloroquine weakened liraglutide-induced autophagy activation and lipid degradation. TFEB has been identified as a key regulator of lysosome biogenesis and autophagy. The protein levels of nuclear TFEB and its downstream targets CTSB and LAMP1 were decreased in hepatocytes treated with PA, and these decreases were reversed by liraglutide treatment. Knockdown of TFEB expression compromised the effects of liraglutide on lysosome biogenesis and hepatic lipid accumulation. Mechanistically, GLP-1R expression was decreased in HFD mouse livers as well as PA-stimulated hepatocytes, and liraglutide treatment reversed the downregulation of GLP-1R expression in vivo and in vitro. Moreover, GLP-1R inhibition could mimic the effect of the TFEB downregulation-mediated decrease in lysosome biogenesis. Thus, our findings suggest that liraglutide attenuated hepatic steatosis via restoring autophagic flux, specifically the GLP-1R-TFEB-mediated autophagy-lysosomal pathway.

scholarly journals Hepatic Lipid Accumulation Induced by a High-fat Diet Is Regulated by Nrf2 Through Multiple Pathways

2021 ◽  
Author(s):  
sheng Qiu ◽  
Zerong Liang ◽  
Qinan Wu ◽  
Miao Wang ◽  
Mengliu Yang ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Lipid Accumulation ◽  
High Fat Diet ◽  
Underlying Mechanism ◽  
Luciferase Assay ◽  
High Fat ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

Abstract BackgroundNuclear factor erythroid 2-related factor 2 (Nrf2) is reportedly involved in hepatic lipid metabolism, but the results are contradictory and the underlying mechanism thus remains unclear. Herein we focused on elucidating the effects of Nrf2 on hepatic adipogenesis and on determining the possible underlying mechanism. We established a metabolic associated fatty liver disease (MAFLD) model in high fat diet (HFD) fed Nrf2 knockout (Nrf2 KO) mice; further, a cell model of lipid accumulation was established using mouse primary hepatocytes (MPHs) treated with free fatty acids (FAs). Using these models, we investigated the relationship between Nrf2 and autophagy and its role in the development of MAFLD.ResultsWe observed that Nrf2 expression levels were up-regulated in patients with MAFLD and diet-induced obese mice. Nrf2 deficiency led to hepatic lipid accumulation in vivo and in vitro, in addition to, promoting lipogenesis mainly by increasing SREBP-1 activity. Moreover, Nrf2 deficiency attenuated autophagic flux and inhibited the fusion of autophagosomes and lysosomes in vivo and in vitro. Weakened autophagy caused reduced lipolysis in the liver. Importantly, Chromatin immunoprecipitation-qPCR (ChIP-qPCR) and dual-luciferase assay results proved that Nrf2 bound to LAMP1 promoter and regulated its transcriptional activity. We accordingly report that Nrf2-LAMP1 interaction has an indispensable role in Nrf2-regulated hepatosteatosis. ConclusionsThese data collectively confirm that Nrf2 deficiency promotes hepatosteatosis by enhancing SREBP-1 activity and attenuating autophagy. To conclude, our data reveal a novel multi-pathway effect of Nrf2 on lipid metabolism in the liver, and we believe that multi-target intervention of Nrf2 signaling is a promising new strategy for the prevention and treatment of MAFLD.

scholarly journals The lncRNA Gm15622 stimulates SREBP-1c expression and hepatic lipid accumulation by sponging the miR-742-3p in mice

2020 ◽  
Vol 61 (7) ◽  
pp. 1052-1064 ◽  
Author(s):  
Minjuan Ma ◽  
Rui Duan ◽  
Lulu Shen ◽  
Mengting Liu ◽  
Yaya Ji ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Lipid Deposition ◽  
In Vivo Models ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Regulatory Circuit ◽  
Murine Liver

Excessive lipid deposition is a hallmark of NAFLD. Although much has been learned about the enzymes and metabolites involved in NAFLD, few studies have focused on the role of long noncoding RNAs (lncRNAs) in hepatic lipid accumulation. Here, using in vitro and in vivo models of NAFLD, we found that the lncRNA Gm15622 is highly expressed in the liver of obese mice fed a HFD and in murine liver (AML-12) cells treated with free fatty acids. Investigating the molecular mechanism in the liver-enriched expression of Gm15622 and its effects on lipid accumulation in hepatocytes and on NAFLD pathogenesis, we found that Gm15622 acts as a sponge for the microRNA miR-742-3p. This sponging activity increased the expression of the transcriptional regulator SREBP-1c and promoted lipid accumulation in the liver of the HFD mice and AML-12 cells. Moreover, further results indicated that metformin suppresses Gm15622 and alleviates NAFLD-associated lipid deposition in mice. In conclusion, we have identified an lncRNA Gm15622/miR-742-3p/SREBP-1c regulatory circuit associated with NAFLD in mice, a finding that significantly advances our insight into how lipid metabolism and accumulation are altered in this metabolic disorder. Our results also suggest that Gm15622 may be a potential therapeutic target for managing NAFLD.

scholarly journals Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway in vivo and in vitro

2021 ◽  
Vol 11 ◽  
Author(s):  
Ting Li ◽  
Ting Fang ◽  
Linxin Xu ◽  
Xiangyang Liu ◽  
Xiaoyu Li ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Liver Steatosis ◽  
Fatty Degeneration ◽  
Hepatic Lipid Accumulation ◽  
Compound C ◽  
Hepatocyte Steatosis ◽  
Autophagy Pathway

Background: Metabolic associated fatty liver disease (MAFLD), characterized by hepatic lipid accumulation and fatty degeneration, is intertwined with obesity and type 2 diabetes mellitus (T2DM). Empagliflozin is a sodium-glucose cotransporter-2 inhibitor that effectively lowers blood glucose, but its effect on MAFLD and associated mechanisms are not fully understood.Methods: Eight-week-old db/db mice, an in vivo model, were administered empagliflozin or saline intragastrically. A hepatocyte steatosis model was established by inducing HL7702 cells with high glucose and palmitic acid and then treated with or without empagliflozin. The autophagy inhibitor (3-methyladenine, 3-MA) and AMP-activated protein kinase (AMPK) activator (AICAR)/inhibitor (Compound C) were used to determine the involvement of AMPK and autophagy in the regulation of lipid accumulation by empagliflozin. Ten-eleven translocation 2 (TET2) knockdown was achieved by siRNA transfection. Hepatic steatosis was evaluated by Oil Red O staining and triglyceride quantification. Immunohistochemistry, immunofluorescence, and western blot were performed to assess protein levels.Results: Empagliflozin alleviated liver steatosis in db/db mice and reduced triglyceride content and lipid accumulation in the hepatocyte steatosis model. Empagliflozin elevated autophagy, accompanied by an increase in p-AMPK and TET2. Both 3-MA and Compound C abolished the ability of empagliflozin to induce autophagy and reduce hepatic steatosis, while these effects could be recapitulated by AICAR treatment. TET2 knockdown resulted in autophagy inhibition and lipid accumulation despite empagliflozin treatment.Conclusion: Empagliflozin improves hepatic steatosis through the AMPK-TET2-autophagy pathway. The use of empagliflozin as a treatment for preventing and treating MAFLD in patients with T2DM warrants further study.

scholarly journals Ginseng seed oil ameliorates hepatic lipid accumulation in vitro and in vivo

2018 ◽  
Vol 42 (4) ◽  
pp. 419-428 ◽  
Author(s):  
Go Woon Kim ◽  
Hee Kyung Jo ◽  
Sung Hyun Chung
Keyword(s):  
Lipid Accumulation ◽  
Seed Oil ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

scholarly journals Qushi Huayu Decoction Inhibits Hepatic Lipid Accumulation by Activating AMP-Activated Protein KinaseIn VivoandIn Vitro

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Qin Feng ◽  
Xiao-jun Gou ◽  
Sheng-xi Meng ◽  
Cheng Huang ◽  
Yu-quan Zhang ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Lipid Accumulation ◽  
Nuclear Protein ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Element Binding Protein ◽  
L02 Cells

Qushi Huayu Decoction (QHD), a Chinese herbal formula, has been proven effective on alleviating nonalcoholic fatty liver disease (NAFLD) in human and rats. The present study was conducted to investigate whether QHD could inhibit hepatic lipid accumulation by activating AMP-activated protein kinase (AMPK)in vivoandin vitro. Nonalcoholic fatty liver (NAFL) model was duplicated with high-fat diet in rats and with free fatty acid (FFA) in L02 cells. Inin vivoexperimental condition, QHD significantly decreased the accumulation of fatty droplets in livers, lowered low-density lipoprotein cholesterol (LDL-c), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels in serum. Moreover, QHD supplementation reversed the HFD-induced decrease in the phosphorylation levels of AMPK and acetyl-CoA carboxylase (ACC) and decreased hepatic nuclear protein expression of sterol regulatory element-binding protein-1 (SREBP-1) and carbohydrate-responsive element-binding protein (ChREBP) in the liver. Inin vitro, QHD-containing serum decreased the cellular TG content and alleviated the accumulation of fatty droplets in L02 cells. QHD supplementation reversed the FFA-induced decrease in the phosphorylation levels of AMPK and ACC and decreased the hepatic nuclear protein expression of SREBP-1 and ChREBP. Overall results suggest that QHD has significant effect on inhibiting hepatic lipid accumulation via AMPK pathwayin vivoandin vitro.

scholarly journals Role of β-adrenergic receptors in regulation of hepatic fat accumulation during aging

2012 ◽  
Vol 213 (3) ◽  
pp. 251-261 ◽  
Author(s):  
Paramita M Ghosh ◽  
Zhen-Ju Shu ◽  
Bing Zhu ◽  
Zhongding Lu ◽  
Yuji Ikeno ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
Hepatic Steatosis ◽  
Lipid Content ◽  
Lipid Accumulation ◽  
Adenylyl Cyclase Activity ◽  
Fat Accumulation ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Hepatic Fat

Excessive fat accumulation in liver (hepatic steatosis) predisposes to hepatic functional and structural impairment and overall metabolic risk. Previous studies noted an association between hepatic steatosis and age in humans and rodents. However, the mechanisms leading to age-associated hepatic fat accumulation remain unknown. Earlier work from our group showed that β-adrenergic receptor (β-AR) levels and β-AR-stimulated adenylyl cyclase activity increase in rat liver during aging. Here we investigated whether age-associated increases in β-AR signaling play a role in augmenting hepatic lipid accumulation. We demonstrate an increase in hepatic lipid content during senescence and a significant correlation between hepatic fat content and stimulation of adenylyl cyclase activity by the β-AR agonist isoproterenol in rat liver. Isoproterenol administration to young and old rodents in vivo increased hepatic lipid accumulation. Furthermore, in vitro overexpression of β1- and β2-AR subtypes in hepatocytes from young rodents increased cellular lipid content, whereas inhibition of β-ARs by receptor subtype-specific inhibitors reduced lipid levels in hepatocytes from senescent animals. Isoproterenol-induced hepatic lipid accumulation in vivo was prevented by the β-AR nonselective blocker propranolol, suggesting a novel therapeutic effect of this class of drugs in hepatic steatosis. Acipimox, which inhibits adipose tissue lipolysis, did not alter isoproterenol-mediated hepatic fat accumulation; thus β-AR responsive hepatic lipid accumulation does not appear to be related primarily to altered lipolysis. These findings suggest that augmented hepatic β-AR signaling during aging may increase lipid accumulation in liver and advocate a possible role for β-adrenergic blockers in preventing or retarding the development of hepatic steatosis.

scholarly journals Dietary Oxysterol, 7-Ketocholesterol Accelerates Hepatic Lipid Accumulation and Macrophage Infiltration in Obese Mice

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiuyang Chang ◽  
Masahiro Koseki ◽  
Ayami Saga ◽  
Kotaro Kanno ◽  
Tomoaki Higo ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Lipid Extraction ◽  
Acid Oxidation ◽  
Chow Diet ◽  
Obese Mice ◽  
Mice Model ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid Accumulation

Non-alcoholic fatty liver disease is strongly associated with obese and type 2 diabetes. It has been reported that an oxidized cholesterol, 7-ketocholesterol (7KC), might cause inflammatory response in macrophages and plasma 7KC concentration were higher in patients with cardiovascular diseases or diabetes. Therefore, we have decided to test whether small amount of 7KC in diet might induce hepatic steatosis and inflammation in two types of obese models. We found that addition of 0.01% 7KC either in chow diet (CD, regular chow diet with 1% cholesterol) or western type diet (WD, high fat diet with 1% cholesterol) accelerated hepatic neutral lipid accumulation by Oil Red O staining. Importantly, by lipid extraction analysis, it has been recognized that triglyceride rather than cholesterol species was significantly accumulated in CD+7KC compared to CD as well as in WD+7KC compared to WD. Immunostaining revealed that macrophages infiltration was increased in CD+7KC compared to CD, and also in WD+7KC compared to WD. These phenotypes were accompanied by inducing inflammatory response and downregulating fatty acid oxidation. Furthermore, RNA sequence analysis demonstrated that 7KC reduced expression of genes which related to autophagy process. Levels of LC3-II protein were decreased in WD+7KC compared to WD. Similarly, we have confirmed the effect of 7KC on acceleration of steatohepatitis in db/db mice model. Collectively, our study has demonstrated that small amount of dietary 7KC contributed to accelerate hepatic steatosis and inflammation in obese mice models.

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