scholarly journals Traditional Chinese Medicine Lingguizhugan Decoction Ameliorate HFD-Induced Hepatic-Lipid Deposition in Mice by Inhibiting STING-Mediated Inflammation in Macrophages

2021 ◽  
Author(s):  
Lin Cao ◽  
Erjin Xu ◽  
Rendong Zheng ◽  
Rongling Zhong ◽  
Fei Huang ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Hepatic Steatosis ◽  
Metabolic Disorders ◽  
Cell Model ◽  
Critical Role ◽  
Signal Pathways ◽  
Lipid Deposition ◽  
Mice Model ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid

Abstract Background: Stimulator of IFN genes (STING) is highly expressed in the livers of non-alcoholic fatty liver disease(NAFLD) patients and HFD induced NAFLD mice model. The STING signaling induced inflammation has been shown to be a critical role in metabolic disorders, such as NAFLD and Type 2 diabetes. Lingguizhugan decoction (LGZG), a Traditional Chinese herbal decoction, has been applied to treat metabolic disorders for many years. However, whether LGZG can alleviate the progression of NAFLD through inhibiting inflammation is not fully understood. This study was to determine the role of STING-mediated inflammation in the HFD- induced hepatic-lipid deposition treated with LGZG.Methods: The anti-inflammatory and anti- hepatic-lipid deposition effects of LGZG in vivo were detected by H&E staining, immunofluorescence and immunochemistry. Mice bone-marrow-derived macrophages (BMDMs) were co-incubated with palmitic acid-induced lipid deposition HepG2 cell model (BMDM+PA-HepG2) and treated with LGZG.STING-specific agonist or blockers respectively to detect whether the activation of STING-mediated pathway is involved in the anti-hepatocyte lipid deposition effect of LGZG. Mitochondrial DNA was detected by real time PCR. The expression of inflammatory cytokines related to STING-TBK1-NF-κB pathway was detected by western blotting and ELISA.Results: LGZG significantly ameliorated HFD induced hepatic steatosis, alleviated insulin resistance (IR) and reduced the oxidative stress. Furthermore, LGZG reduced hepatic mitochondrial damage and mitochondrial DNA release, which corresponded to reducing the expression of STING as well as the the infiltration of STING-positive Kupffer cells in the liver of HFD fed mice. LGZG directly inhibited the activation of STING-TBK1-NF-κB pathway in BMDM induced by DMXAA, LPS, thereby reducing the release of IFNβ and TNFα. Co-incubation LGZG treated BMDM and PA-stimulated HepG2 significantly reduced PA-induced lipid deposition in HepG2 cells by inhibiting STING- mediated signal pathways. Conclusion: This study demonstrates that LGZG can ameliorate HFD-induced hepatic -lipid deposition through inhibiting STING-TBK1-NF-κB pathway in macrophages, which provides novel insight for elucidating the molecular mechanism of LGZG alleviating HFD induced hepatic steatosis.

scholarly journals Traditional Chinese medicine Lingguizhugan decoction ameliorate HFD-induced hepatic-lipid deposition in mice by inhibiting STING-mediated inflammation in macrophages

2022 ◽  
Vol 17 (1) ◽  
Author(s):  
Lin Cao ◽  
Erjin Xu ◽  
Rendong Zheng ◽  
Zhili Zhangchen ◽  
Rongling Zhong ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mouse Liver ◽  
Metabolic Disorders ◽  
Culture Supernatant ◽  
Lipid Deposition ◽  
Hepatic Lipid ◽  
Liver Macrophages ◽  
Dna Release ◽  
Critical Components

Abstract Background Stimulator of IFN genes (STING) is highly expressed in the livers of non-alcoholic fatty liver disease (NAFLD) patients and high fat diet (HFD) induced NAFLD mice model. The STING signaling-mediated inflammation has been shown to play a critical role in metabolic disorders. Lingguizhugan decoction (LGZG), a Traditional Chinese herbal decoction, has been applied to treat metabolic disorders for many years. However, whether LGZG can alleviate the progression of NAFLD through inhibiting inflammation remains unclear. This study was to determine the role of STING-mediated inflammation in the HFD-induced hepatic-lipid deposition treated with LGZG. Methods The anti-inflammatory and anti-steatotic effects of LGZG in vivo were detected by H&E staining, immunofluorescence and immuno-chemistry. Mice bone-marrow-derived macrophages (BMDMs) and primary liver macrophages were treated with STING-specific agonist (DMXAA), LGZG and its critical components respectively. The treated culture supernatant of BMDMs and primary liver macrophages from each group was co-cultured with palmitic acid-treated mouse primary hepatocytes or mouse liver cell line AML-12 respectively to detect whether the activation of STING-mediated pathway is involved in the anti-steatotic effect of LGZG. The hepatocyte lipid deposition in vivo and in vitro were detected by oil red staining. Mitochondrial DNA release of mouse liver extracts were detected by real time PCR. The expression of proteins and inflammatory cytokines related to STING-TBK1-NF-κB pathway was detected by western blotting and ELISA. Results LGZG significantly ameliorated HFD induced hepatic steatosis, oxidative stress, hepatic mitochondrial damage and mitochondrial DNA release, which was correlated with reduction of the expression level of STING as well as the infiltration of STING-positive macrophages in the livers of HFD fed mice. The critical components of LGZG directly inhibited the activation of STING-TBK1-NF-κB pathway in liver macrophages induced by DMXAA, LPS, thereby reducing the release of IFNβ and TNFα. Co-incubating the culture supernatant of LGZG treated liver macrophages and PA-stimulated hepatocytes significantly inhibited the PA-induced lipid deposition. Conclusion This study demonstrates that LGZG can ameliorate HFD-induced hepatic-lipid deposition through inhibiting STING-TBK1-NF-κB pathway in liver macrophages, which provides novel insight for elucidating the molecular mechanism of LGZG alleviating HFD induced hepatic steatosis.

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 URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and BAT whitening in mice

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
Y Tanaka ◽  
T Nagoshi ◽  
A Yoshii ◽  
Y Oi ◽  
H Takahashi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Hepatic Steatosis ◽  
Critical Role ◽  
Selective Inhibition ◽  
Selective Inhibitor ◽  
Obese Mice ◽  
Alcoholic Fatty Liver ◽  
Brown Adipose

Abstract Background Accumulating evidence suggests that high uric acid is strongly associated with obesity and metabolic syndrome and drives the development of non-alcoholic fatty liver disease (NAFLD) and insulin resistance. Although urate transporter-1 (URAT1), which is primarily expressed in the kidney, plays a critical role in the development of hyperuricemia, its pathophysiological implication in NAFLD and insulin resistance remains unclear. Objectives We hypothesizes that URAT1 plays an important role in obesity-induced metabolic disorders, and URAT1-selective inhibitor treatment ameliorates systemic insulin resistance, NAFLD and adipose tissue dysfunction using diet-induced obese mice. Methods Mice fed a high-fat diet (HFD) for 16 to 18 weeks or a normal-fat diet (NFD) were treated with or without a novel oral URAT1-selective inhibitor (dotinurad [50 mg/kg/day]) for another 4 weeks. Results Dotinurad administration significantly ameliorated HFD-induced obesity and insulin resistance. We found that URAT1 was also expressed in the liver and brown adipose tissue (BAT) other than kidney. HFD markedly induced NAFLD, which was characterized by severe hepatic steatosis, as well as the elevation of serum ALT activity and tissue inflammatory cytokine genes (Ccl2 and TNFα), all of which were attenuated by dotinurad. Likewise, HFD significantly increased URAT1 expression in BAT, resulting in the lipid accumulation (whitening of BAT) and increased production of tissue reactive oxygen species, which were reduced by dotinurad via UCP1 activation. Conclusions A novel URAT1-selective inhibitor, dotinurad, ameliorates insulin resistance by attenuating hepatic steatosis and promoting rebrowning of lipid-rich BAT in HFD-induced obese mice. URAT1 serves as a key regulator of the pathophysiology of metabolic syndrome, and may be a new therapeutic target for insulin-resistant individuals, particularly those with concomitant NAFLD. FUNDunding Acknowledgement Type of funding sources: None.

scholarly journals Hepatic Krüppel-like factor 16 (KLF16) targets PPARα to improve steatohepatitis and insulin resistance

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321774
Author(s):  
Nannan Sun ◽  
Chuangpeng Shen ◽  
Lei Zhang ◽  
Xiaojie Wu ◽  
Yuanyuan Yu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Redox Balance ◽  
Luciferase Reporter ◽  
Lipid Deposition ◽  
Mitochondrial Stress ◽  
Hepatic Lipid ◽  
Gene Assay

ObjectiveImpaired hepatic fatty acids oxidation results in lipid accumulation and redox imbalance, promoting the development of fatty liver diseases and insulin resistance. However, the underlying pathogenic mechanism is poorly understood. Krüppel-like factor 16 (KLF16) is a transcription factor that abounds in liver. We explored whether and by what mechanisms KLF16 affects hepatic lipid catabolism to improve hepatosteatosis and insulin resistance.DesignKLF16 expression was determined in patients with non-alcoholic fatty liver disease (NAFLD) and mice models. The role of KLF16 in the regulation of lipid metabolism was investigated using hepatocyte-specific KLF16-deficient mice fed a high-fat diet (HFD) or using an adenovirus/adeno-associated virus to alter KLF16 expression in mouse primary hepatocytes (MPHs) and in vivo livers. RNA-seq, luciferase reporter gene assay and ChIP analysis served to explore the molecular mechanisms involved.ResultsKLF16 expression was decreased in patients with NAFLD, mice models and oleic acid and palmitic acid (OA and PA) cochallenged hepatocytes. Hepatic KLF16 knockout impaired fatty acid oxidation, aggravated mitochondrial stress, ROS burden, advancing hepatic steatosis and insulin resistance. Conversely, KLF16 overexpression reduced lipid deposition and improved insulin resistance via directly binding the promoter of peroxisome proliferator-activated receptor α (PPARα) to accelerate fatty acids oxidation and attenuate mitochondrial stress, oxidative stress in db/db and HFD mice. PPARα deficiency diminished the KLF16-evoked protective effects against lipid deposition in MPHs. Hepatic-specific PPARα overexpression effectively rescued KLF16 deficiency-induced hepatic steatosis, altered redox balance and insulin resistance.ConclusionsThese findings prove that a direct KLF16–PPARα pathway closely links hepatic lipid homeostasis and redox balance, whose dysfunction promotes insulin resistance and 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.

scholarly journals Functional multispectral optoacoustic tomography imaging of hepatic steatosis development in mice

2020 ◽  
Author(s):  
Shan Huang ◽  
Andreas Blutke ◽  
Annette Feuchtinger ◽  
Uwe Klemm ◽  
Robby Zachariah Tom ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Critical Role ◽  
Label Free ◽  
Alcoholic Fatty Liver ◽  
Optoacoustic Tomography ◽  
Imaging Tool ◽  
Functional Relations ◽  
Prevalence Of Obesity ◽  
Clearance Kinetics

AbstractThe increasing worldwide prevalence of obesity, fatty liver diseases, as well as the emerging understanding of the importance of lipids in multi-faceted aspects of various other diseases is generating significant interest in lipid research. Lipid visualization in particular can play a critical role in understanding functional relations in lipid metabolism. In this study, we investigate the potential of multispectral optoacoustic tomography (MSOT) as a novel modality to non-invasively visualize lipids in laboratory mice. Using an obesity-induced non-alcoholic fatty liver disease (NAFLD) mouse model, we examined whether MSOT could detect and differentiate different grades of hepatic steatosis and monitor the accumulation of lipids in the liver quantitatively over time, without the use of contrast agents, i.e. in label free mode. Moreover, we demonstrate the efficacy of using the real-time clearance kinetics of indocyanine green (ICG) in the liver as a biomarker to evaluate the organs’ function and assess the severity of NAFLD. This study demonstrates MSOT as an efficient imaging tool for lipid visualization in preclinical studies, particularly for the assessment of NAFLD.

scholarly journals Aerobic Exercise Promotes the Expression of ATGL and Attenuates Inflammation to Improve Hepatic Steatosis via lncRNA SRA

2021 ◽  
Author(s):  
Baoai Wu ◽  
Yiming Tian ◽  
Chong Xu ◽  
Yu Zeng ◽  
Feng Yan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Aerobic Exercise ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Inflammatory Factors ◽  
Control Group ◽  
Inflammatory Factor ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid

Abstract The role of aerobic exercise in preventing and improving non-alcoholic fatty liver has been widely established. SRA is a long non-coding RNA, which has received increasing attention due to its important role in lipid metabolism. However, it is unclear whether aerobic exercise can prevent and treat hepatic lipid accumulation via SRA. The mice were randomly divided into three groups as follows, normal control group (NC), high-fat diet group (HFD), and high-fat diet plus aerobic exercise (8weeks, 6 days/ week, 18 m/ min for 50 min, 6% slope) group (HAE). After 8 weeks, the mice in the HAE group showed significant improvement in hepatic steatosis. Body weight as well as blood TC, LDL-C, and liver TG levels were significantly lower in the HAE group than in the HFD group. Compared with the HFD group, the expression of SRA was markedly suppressed and the expression of ATGL was significantly increased in the HAE group. Additionally, the JNK/P38 signaling was inhibited, the pro-inflammatory factors were down-regulated, and the anti-inflammatory factor was increased. The results of this study provided new support for aerobic exercise to improve hepatic lipid metabolism via lncRNA.

scholarly journals CARF (CDKN2AIP) Regulates Hepatic Lipid Metabolism and Protects Against Development of Non-Alcoholic Fatty Liver Diseases

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A284-A284
Author(s):  
Kamrul M Hasan ◽  
Meher Parveen ◽  
Alondra Pena ◽  
Erick Galdamez Calles ◽  
Marvy Gergis ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Mouse Model ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Hepg2 Cells ◽  
Liver Diseases ◽  
Hepatic Lipid Metabolism ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid

Abstract Non-alcoholic fatty liver diseases (NAFLD) is the most common form of liver diseases in the USA with 30–40% of American being affected and about 12% with nonalcoholic steatohepatitis (NASH), a leading cause of end-stage liver diseases. NAFLD has been linked with insulin resistance, type2 diabetes, obesity, and cardiovascular diseases but molecular mechanisms underlying the development of NAFLD and its association with metabolic syndromes are poorly understood. In this study, we explored the role of CARF (collaborator of ARF) also known as CDKN2AIP, a novel gene of ARF-MDM2-p53 pathway in the development of NAFLD. It has been shown that, p53, beyond its tumor suppressor functions, can regulate the cellular glucose and lipid metabolism and its activation has been reported to induce hepatic steatosis in mice. However, as a regulator of p53 pathway, the role of CARF in the lipid metabolism and associated metabolic diseases has not been studied yet. Using high-fat diet (HFD) fed obesity mouse model of NAFLD we found that the expression of CARF along with Sirt1, pAMPK, and pACC was significantly decreased in the HFD induced fatty livers compared to control. Similarly, CARF expression was also down-regulated in palmitate (PA)-treated HepG2 cells, an in vitro model of steatosis. We also observed that shRNA mediated knockdown or lentiviral vector mediated overexpression of CARF induced or reduced the endogenous fat accumulation, respectively, in HepG2 cells, suggesting that CARF expression is negatively regulated in NAFLD. Additionally, we performed RNA seq analysis after CARF silencing in HepG2 cells and demonstrated that silencing of CARF altered the expression of genes regulating hepatic de novo lipogenesis, beta-oxidation, and lipid secretion all of which favor the accumulation of fat in the hepatocytes. Furthermore, genes associated with mitochondrial functions such as the TCA cycle and oxidative phosphorylation were also altered which could play a role in the development of NAFLD. Finally, we demonstrated that AAV mediated hepatic overexpression of CARF in HFD fed mouse model significantly reduced the fat accumulation in the liver as evident by H&E staining of liver sections and intrahepatic triglyceride level. Altogether we conclude that CARF plays a vital role in hepatic lipid metabolism and its downregulation perturbs lipid homeostasis leading to hepatic steatosis and the development of NAFLD.

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