scholarly journals Lanzhang Granules Ameliorate Nonalcoholic Fatty Liver Disease by Regulating the PPARα Signaling Pathway

2022 ◽  
Vol 2022 ◽  
pp. 1-15
Author(s):  
Ping Huang ◽  
Lili Yang ◽  
Yang Liu ◽  
Yuwei Jiang ◽  
Yiping Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Liver Disease ◽  
Western Blot ◽  
Fatty Liver ◽  
Signaling Pathway ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Rt Pcr ◽  
Nonalcoholic Fatty Liver

Background. There is still a lack of effective therapeutic drugs for nonalcoholic fatty liver disease (NAFLD) to date. In this study, we applied mouse model experiments to clarify the effect of Chinese herbal medicine “Lanzhang Granules (LZG)” on NAFLD and further explore the potential mechanism to provide an alternative method for NAFLD treatment. Methods. Male C57BL/6J mice were fed with a high-fat diet (HFD) for twenty-two weeks to induce the NAFLD model. LZG intervention was then performed by gavage daily for another eight weeks. At the end of the treatment, serum and liver tissues were collected. Serum biochemical indexes, insulin levels, and liver histopathology were measured to assess the effect of LZG on NAFLD. The liver tissues were then analyzed by RNA sequence for differentially expressed genes and signaling pathways. Results were further analyzed by Protein-Protein Interaction (PPI) networks between the LZG and model groups. The selected different genes and signaling pathways were further verified by RT-PCR and Western blot analysis. Moreover, alpha mouse liver 12 (AML12) cells with lipid accumulation induced by fatty acid were treated with LZG, Fenofibrate (PPARα agonist), or Gw6471 (PPARα antagonist) to confirm the potential pharmacological mechanism. Results. LZG was found to downregulate liver weight, body weight, liver index, and serum levels of ALT, AST, and serum lipid in HFD-induced NAFLD mice. HE and Oil Red O staining showed the improvement of hepatic steatosis and inflammatory infiltration in the mice with LZG treatment. The homeostasis model assessment-insulin resistance (HOMA-IR) index indicated that LZG improved the insulin resistance of NAFLD mice. The RNA sequencing and PPI analysis confirmed the role of LZG in lipid metabolism regulation and identified the peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway as one of the major underlying mechanisms. Western blot and RT-PCR results verified the regulatory effect of LZG on the PPARα pathway, including the upregulation of PPARα, acyl-coenzyme A oxidase 1 (ACOX1), and enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase (EHHADH) and the downregulation of TNFα. In vitro experiments showed the effect of LZG in improving lipid accumulation and cell viability in AML12 cells induced by fatty acids, which were alleviated by Gw6471 coincubation. Gw6471could also reverse the transcription of PPAR target genes ACOX1 and EHHADH, which were upregulated by LZG treatment. Conclusion. LZG can improve NAFLD in mice or cell models. A major underlying mechanism may be the regulation of the PPARα signaling pathway to improve lipid metabolism and inhibit the inflammatory response. This study will help to promote the clinical application of LZG for the treatment of NAFLD.

scholarly journals SGL 121 Attenuates Nonalcoholic Fatty Liver Disease through Adjusting Lipid Metabolism Through AMPK Signaling Pathway

2020 ◽  
Vol 21 (12) ◽  
pp. 4534
Author(s):  
Da Eun Kim ◽  
Bo Yoon Chang ◽  
Byeong Min Jeon ◽  
Jong In Baek ◽  
Sun Chang Kim ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Signaling Pathway ◽  
Hepg2 Cells ◽  
Fatty Liver Disease ◽  
Fatty Acid Synthase ◽  
Density Lipoprotein ◽  
Nonalcoholic Fatty Liver

A ginsenoside F2-enhanced mixture (SGL 121) increases the content of ginsenoside F2 by biotransformation. In the present study, we investigated the effect of SGL 121 on nonalcoholic fatty liver disease (NAFLD) in vitro and in vivo. High-fat, high-carbohydrate-diet (HFHC)-fed mice were administered SGL 121 for 12 weeks to assess its effect on improving NAFLD. In HepG2 cells, SGL 121 acted as an antioxidant, a hepatoprotectant, and had an anti-lipogenic effect. In NAFLD mice, SGL 121 significantly improved body fat mass; levels of hepatic triglyceride (TG), hepatic malondialdehyde (MDA), serum total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL); and activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In HepG2 cells, induced by oxidative stress, SGL 121 increased cytoprotection, inhibited reactive oxygen species (ROS) production, and increased antioxidant enzyme activity. SGL 121 activated the Nrf2/HO-1 signaling pathway and improved lipid accumulation induced by free fatty acids (FFA). Sterol regulatory element-binding protein-1 (SREBP-1) and fatty acid synthase (FAS) expression was significantly reduced in NAFLD-induced liver and HepG2 cells treated with SGL 121. Moreover, SGL 121 activated adenosine monophosphate-activated protein kinase (AMPK), which plays an important role in the regulation of lipid metabolism. The effect of SGL 121 on the improvement of NAFLD seems to be related to its antioxidant effects and activation of AMPK. In conclusion, SGL 121 can be potentially used for the treatment of NAFLD.

scholarly journals Dietary Blueberry and Bifidobacteria Attenuate Nonalcoholic Fatty Liver Disease in Rats by Affecting SIRT1-Mediated Signaling Pathway

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Tingting Ren ◽  
Chao Huang ◽  
Mingliang Cheng
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Signaling Pathway ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Control Group ◽  
Nonalcoholic Fatty Liver ◽  
Blueberry Juice ◽  
Group A ◽  
Better Than

NAFLD model rats were established and divided into NAFLD model (MG group), SIRT1 RNAi (SI group), blueberry juice (BJ group), blueberry juice + bifidobacteria (BJB group), blueberry juice + SIRT1 RNAi (BJSI group), and blueberry juice + bifidobacteria + SIRT1 RNAi groups (BJBSI group). A group with normal rats was a control group (CG). BJB group ameliorated NAFLD, which was better than BJ group (P<0.05). The lipid accumulation was lower in CG, BJ, and BJB groups than that in MG, SI, BJSI, and BJBSI groups (P<0.05). The levels of SIRT1 and PPAR-αwere higher in CG, BJ, and BJB groups than those in MG, SI, BJSI, and BJBSI groups (P<0.05). The levels of SREBP-1c were lower in CG, BJ, and BJB groups than those in MG, SI, BJSI, and BJBSI groups (P<0.05). The biochemical indexes SOD, GSH, and HDL-c were improved from CG to BJB group (P<0.05). Inversely, the levels of AST and ALT, TG, TC, LDL-c, and MDA were decreased from CG to BJB group (P<0.05). These changes enhance antioxidative capability and biochemical index of rats. Blueberry juice and bifidobacteria improve NAFLD by activating SIRTI-mediating signaling pathway.

scholarly journals 5-ALA ameliorates hepatic steatosis through AMPK signaling pathway

2017 ◽  
Vol 59 (2) ◽  
pp. 121-128 ◽  
Author(s):  
Haoyong Yu ◽  
Mingliang Zhang ◽  
Yunqin Ma ◽  
Junxi Lu ◽  
Jiemin Pan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Signaling Pathway ◽  
Fatty Liver Disease ◽  
Aminolevulinic Acid ◽  
Therapeutic Effects ◽  
Nonalcoholic Fatty Liver ◽  
Ampk Signaling

5-Aminolevulinic acid (5-ALA), the first compound in the porphyrin synthesis pathway, has been reported to ameliorate the diabetic state in Otsuka Long-Evans Tokushima Fatty rats by reducing fat pad weight in the retroperitoneal region. Dietary supplementation with 5-ALA has additionally demonstrated the capacity to lower blood glucose and HbA1c levels among subjects with diabetes. The etiology of nonalcoholic fatty liver disease (NAFLD) is complex and its typical characteristics include obesity and insulin resistance. As 5-ALA supplementation has previously normalized glucose and insulin resistance, we sought to investigate whether 5-ALA had potential therapeutic effects on NAFLD and elucidate the signal pathway mediating these effects. To explore these questions, we fed C57BL/6J mice a high-fat diet (HFD) to induce a fatty liver disease and supplemented the diet-induced obese (DIO) mice with 5-ALA. The mice in the presence of 5-ALA demonstrated a decrease in body weight and hepatic lipid content and moderate improvement in glucose homeostasis compared to untreated controls. Further, we found that 5-ALA activated AMPK signaling pathway, which was correlated with enhanced lipolysis and fatty acid β-oxidation. Human hepatocarcinoma cells (HepG2 cells) treated with 5-ALA were additionally used to investigate the mechanics of 5-ALA. Treated cells had a higher expression of lipolysis-related genes, including PGC-1α. Our data indicated that 5-ALA might represent a novel compound that could be useful for the treatment of nonalcoholic fatty liver disease (NAFLD), likely through the restoration of phosphorylation levels of AMPK (Thr172) and acetyl-CoA (ACC) (Ser79), further enhanced PGC1α and CPT1α expression.

scholarly journals Jwa Kum Whan Attenuates Nonalcoholic Fatty Liver Disease by Modulating Glucose Metabolism and the Insulin Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Dong-Woo Lim ◽  
Hyuck Kim ◽  
Seung-Jun Lee ◽  
Ga-Ram Yu ◽  
Jai-Eun Kim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Glucose Metabolism ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Fatty Liver Disease ◽  
Insulin Signaling Pathway ◽  
Nonalcoholic Fatty Liver

Over the last decade, the link between nonalcoholic fatty liver disease (NAFLD) and insulin resistance has attracted considerable attention. Caused by chronic hyperglycemic stress, insulin resistance (IR) impairs insulin signal transduction and leads to the development of NAFLD. Jwa Kum Whan (JKW), a herbal formula in Traditional Korean Medicine, consists of two medicinal herbs that possess notable effects against hyperglycemia and IR. In this study, we sought to determine the pharmacological effects of JKW, and the mechanisms responsible, on hepatic steatosis in free fatty acids (FFAs)-stimulated HepG2 cells and in high-fat diet (HFD)-fed obese mice. Treatment with JKW significantly decreased intracellular lipid accumulation in vitro. Furthermore, JKW significantly triggered the phosphorylation of insulin receptor substrate-1 (IRS-1) and phosphoinositide 3-kinase (PI3K) and modulated glucose and lipid metabolism via an AMP-activated protein kinase (AMPK) signaling pathway. Analysis of serum parameters in HFD-fed mice showed that JKW improved glucose levels and insulin resistance index (HOMA-IR). In addition, JKW successfully reduced hepatic triglyceride (TG) and cholesterol accumulation. Our results suggest that JKW alleviates NAFLD by modulating the insulin signaling pathway and glucose metabolism. These findings provide a scientific rationale for the potential use of JKW for the treatment and prevention of NAFLD.

The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance

2010 ◽  
Vol 298 (3) ◽  
pp. G440-G445 ◽  
Author(s):  
Tim C. M. A. Schreuder ◽  
Hendrik A. Marsman ◽  
Martin Lenicek ◽  
Jochem R. van Werven ◽  
Aart J. Nederveen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Liver Disease ◽  
Fatty Liver ◽  
Bile Salt ◽  
Nonalcoholic Fatty Liver Disease ◽  
Plasma Levels ◽  
Fatty Liver Disease ◽  
Nonalcoholic Fatty Liver ◽  
Homa Score

Intestinal FGF19 has emerged as a novel endocrine regulator of hepatic bile salt and lipid metabolism. In patients with nonalcoholic fatty liver disease (NAFLD) hepatic lipid metabolism is deranged. A possible role of FGF19 in NAFLD has not been reported yet. In this study, we assessed intestinal FGF19 production and the hepatic response to FGF19 in NAFLD patients with and without insulin resistance [homeostasis model of assessment (HOMA) score ≥2.5 ( n = 12) and HOMA score <2.5 ( n = 8), respectively]. To this end, NAFLD patients received a standardized oral fat challenge. Postprandial excursions of triglycerides, bile salts, and FGF19 were monitored, and plasma levels of a marker for bile salt synthesis (7α-hydroxy-4-cholesten-3-one) were determined. Fasted FGF19 levels were comparable in a control group of healthy volunteers ( n = 15) and in NAFLD patients (0.26 ± 0.28 vs. 0.18 ± 0.09 ng/ml, respectively, P = 0.94). Postprandial FGF19 levels in both controls and NAFLD patients peaked between 3–4 h and were three times higher than baseline levels. The areas under the postprandial FGF19 curve were similar in controls and in the HOMA score-based NAFLD subgroups. In NAFLD patients with HOMA score <2.5, the postprandial increase in plasma FGF19 was accompanied by a lowering of plasma levels of 7α-hydroxy-4-cholesten-3-one (−30%, P = 0.015). This anticipated decline was not observed in insulin-resistant NAFLD patients (+10%, P = 0.22). In conclusion, patients with NAFLD show an unimpaired intestinal FGF19 production. However, the hepatic response to FGF19 is impaired in NAFLD patients with insulin resistance (HOMA score ≥2.5). This impaired hepatic response to FGF19 may contribute to the dysregulation of lipid homeostasis in NAFLD.

scholarly journals Downregulated microRNA-130b-5p prevents lipid accumulation and insulin resistance in a murine model of nonalcoholic fatty liver disease

2020 ◽  
Vol 319 (1) ◽  
pp. E34-E42
Author(s):  
Xiaonan Liu ◽  
Shuhong Chen ◽  
Lanju Zhang
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Luciferase Reporter ◽  
Akt Pathway ◽  
Model Assessment ◽  
Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) amplifies the risk of various liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis, and ultimately hepatocellular carcinoma. Accumulating evidence suggests the involvement of aberrant microRNAs (miRNAs or miRs) in the activation of cellular stress, inflammation, and fibrogenesis in hepatic cells at different stages of NAFLD and liver fibrosis. Here, we explored the potential role of miR-130b-5p in the pathogenesis of NAFLD, including lipid accumulation and insulin resistance, as well as the underlying mechanism. Initially, the expression of miR-130b-5p and insulin-like growth factor binding protein 2 (IGFBP2) was examined in the established high-fat diet-induced NAFLD mouse models. Then, the interaction between miR-130b-5p and IGFBP2 was validated using dual luciferase reporter assay. The effects of miR-130b-5p and IGFBP2 on lipid accumulation and insulin resistance, as well as the AKT pathway-related proteins, were evaluated using gain or loss-of-function approaches. miR-130b-5p was upregulated, and IGFBP2 was downregulated in liver tissues of NAFLD mice. miR-130b-5p targeted IGFBP2 and downregulated its expression. MiR-130b-5p inhibition or IGFBP2 overexpression reduced the expression of SREBP-1, LXRα, ChREBP, stearoyl CoA desaturase 1, acetyl CoA carboxylase 1, and fatty acid synthase, and levels of fasting blood glucose, fasting insulin, and homeostasis model assessment-insulin resistance, while increasing the ratio of p-AKT/AKT in NAFLD mice. Overall, downregulation of miR-130b-5p can prevent hepatic lipid accumulation and insulin resistance in NAFLD by activating IGFBP2-dependent AKT pathway, highlighting the potential use of anti-miR-130b-5p as therapeutic approaches for the prevention and treatment of NAFLD.

scholarly journals TMAO Stimulate Inflammation and Lipid Accumulation via NF-κB Signaling Pathway in Nonalcoholic Fatty Liver Disease

2021 ◽  
Author(s):  
zhijun chen ◽  
Jiale Zhang ◽  
Qian Cheng ◽  
Xiangsheng Cai ◽  
RuiTian Xie ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Signaling Pathway ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Intestinal Flora ◽  
Common Disease ◽  
Nonalcoholic Fatty Liver

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is a common disease and it is commonly associated with obesity. Trimethylamine N-oxide (TMAO) is a metabolite of intestinal flora generated in liver by flavin-containing monooxygenase 3 (FMO3), which has been widely studied in cardiovascular diseases and obesity. However, the mechanism of TMAO reacted on liver remains unclear. This study aimed to determine TMAO activated hepatitis inflammation and lipid accumulation which was associated with nuclear factor kappa B (NF-κB) signaling pathway in vitro. ResultsThe present study showed that TMAO in 50μM markedly increased the LO2 cells function and decreased the cells inflammation. However, over the concentration of 200μM in TMAO, cells inflammation was increased and function was declined apparently. In addition, TMAO promoted lipid accumulation. Mechanistically, this change was accompanied by the activation of NF-κB signaling pathway. Furthermore, blocking NF-κB by SN50 was significantly increased in lipid accumulation and apoptosis. SN50 was markedly decreased the protein expression stimulating by TMAO.ConclusionsOverall, the result suggested that TMAO promotes cells inflammation and lipid accumulation in hepatocytes and it might be associated with NF-κB signaling pathway.

scholarly journals How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?

2021 ◽  
Vol 15 (1) ◽  
pp. 21-35
Author(s):  
Yana Geng ◽  
Klaas Nico Faber ◽  
Vincent E. de Meijer ◽  
Hans Blokzijl ◽  
Han Moshage
Keyword(s):  
Lipid Metabolism ◽  
Liver Disease ◽  
Fatty Liver ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Lipid Uptake ◽  
Cellular Mechanisms ◽  
Alcoholic Fatty Liver ◽  
Lipid Species ◽  
Alcoholic Fatty Liver Disease

Abstract Background Non-alcoholic fatty liver disease (NAFLD), characterized as excess lipid accumulation in the liver which is not due to alcohol use, has emerged as one of the major health problems around the world. The dysregulated lipid metabolism creates a lipotoxic environment which promotes the development of NAFLD, especially the progression from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH). Purposeand Aim This review focuses on the mechanisms of lipid accumulation in the liver, with an emphasis on the metabolic fate of free fatty acids (FFAs) in NAFLD and presents an update on the relevant cellular processes/mechanisms that are involved in lipotoxicity. The changes in the levels of various lipid species that result from the imbalance between lipolysis/lipid uptake/lipogenesis and lipid oxidation/secretion can cause organellar dysfunction, e.g. ER stress, mitochondrial dysfunction, lysosomal dysfunction, JNK activation, secretion of extracellular vesicles (EVs) and aggravate (or be exacerbated by) hypoxia which ultimately lead to cell death. The aim of this review is to provide an overview of how abnormal lipid metabolism leads to lipotoxicity and the cellular mechanisms of lipotoxicity in the context of NAFLD.

Sign in / Sign up

Export Citation Format

Share Document