scholarly journals The Role of TM6SF2 in Non-Alcoholic Fatty Liver Disease: From Mechanisms To Therapeutic Strategy

2021 ◽  
Author(s):  
Zuyin Li ◽  
Gang Wu ◽  
Chen Qiu ◽  
Zhijie Zhou ◽  
Yupeng Wang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Acid Metabolism ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Acid Metabolism ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

Abstract Background and aims : Lack of effective pharmacotherapies for nonalcoholic fatty liver disease (NAFLD) is mainly attributed to an insufficient research on its pathogenesis. In this paper, we investigated the role of TM6SF2 on fatty acid metabolism in the background of fatty liver, and proposed the possible therapeutic strategies of NAFLD caused by TM6SF2 deficiency. Methods Liver samples collected from both NAFLD mouse models and human subjects, and RNA-seq data retrieved from GEO database were used to evaluate the expression of TM6SF2 in NAFLD. Knockdown of TM6SF2 was performed for clarifying the mechanistic basis of hepatic lipid accumulation in NAFLD. After confirming that TM6SF2 deficiency would cause an abnormality in fatty acid metabolism, MK-4074 administration served as the therapeutic intervention to evaluate its effect on NAFLD caused by TM6SF2 deficiency. Results Hepatic TM6SF2 levels are elevated in both NAFLD patients and mouse NAFLD models. In vivo and in vitro experiments confirmed that TM6SF2 knockdown increases intracellular lipid deposition due to dysregulated fatty acid metabolism in the context of TM6SF2 deficiency, being characterized by enhanced fatty acid uptake and synthesis, accompanied by impaired fatty acid oxidation. Moreover, MK-4074 treatment could reverse the NAFLD phenotypes caused by TM6SF2 deficiency. Conclusions TM6SF2 deficiency enhanced hepatic lipid accumulation through dysregulated fatty acid metabolism and MK-4074 treatment could alleviate the NAFLD phenotypes caused by TM6SF2 deficiency.

scholarly journals Understanding the Role of Exercise in Nonalcoholic Fatty Liver Disease: ERS-Linked Molecular Pathways

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Yong Zou ◽  
Zhengtang Qi
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Molecular Pathways ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

Nonalcoholic fatty liver disease (NAFLD) is globally prevalent and characterized by abnormal lipid accumulation in the liver, frequently accompanied by insulin resistance (IR), enhanced hepatic inflammation, and apoptosis. Recent studies showed that endoplasmic reticulum stress (ERS) at the subcellular level underlies these featured pathologies in the development of NAFLD. As an effective treatment, exercise significantly reduces hepatic lipid accumulation and thus alleviates NAFLD. Confusingly, these benefits of exercise are associated with increased or decreased ERS in the liver. Further, the interaction between diet, medication, exercise types, and intensity in ERS regulation is more confusing, though most studies have confirmed the benefits of exercise. In this review, we focus on understanding the role of exercise-modulated ERS in NAFLD and ERS-linked molecular pathways. Moderate ERS is an essential signaling for hepatic lipid homeostasis. Higher ERS may lead to increased inflammation and apoptosis in the liver, while lower ERS may lead to the accumulation of misfolded proteins. Therefore, exercise acts like an igniter or extinguisher to keep ERS at an appropriate level by turning it up or down, which depends on diet, medications, exercise intensity, etc. Exercise not only enhances hepatic tolerance to ERS but also prevents the malignant development of steatosis due to excessive ERS.

Simultaneous co-assembly of fenofibrate and ketoprofen peptide for the dual-targeted treatment of nonalcoholic fatty liver disease (NAFLD)

2020 ◽  
Vol 56 (36) ◽  
pp. 4922-4925 ◽  
Author(s):  
Zhongyan Wang ◽  
Chuanrui Ma ◽  
Yuna Shang ◽  
Lijun Yang ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Inflammatory Responses ◽  
Targeted Treatment ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

An ingenious co-assembled nanosystem based on fenofibrate and ketoprofen peptide for the dual-targeted treatment of NAFLD by reducing hepatic lipid accumulation and inflammatory responses.

scholarly journals Macrovesicular steatosis in nonalcoholic fatty liver disease is a consequence of purine nucleotide cycle driven fumarate accumulation

2020 ◽  
Author(s):  
Matthew C. Sinton ◽  
Baltasar Lucendo Villarin ◽  
Jose Meseguer Ripolles ◽  
Sara Wernig-Zorc ◽  
John P. Thomson ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Purine Nucleotide ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Purine Nucleotide Cycle

SummaryNonalcoholic fatty liver disease (NAFLD) affects ~88% of obese individuals and is characterised by hepatic lipid accumulation. Mitochondrial metabolic dysfunction is a feature of NAFLD. We used a human pluripotent stem cell-based system to determine how mitochondrial dysfunction is linked to hepatic lipid accumulation. We induced lipid accumulation in hepatocyte-like cells (HLCs) using lactate, pyruvate and octanoate (LPO). Transcriptomic analysis revealed perturbation of mitochondrial respiratory pathways in LPO exposed cells. Using 13C isotopic tracing, we identified truncation of the TCA cycle in steatotic HLCs. We show that increased purine nucleotide cycle (PNC) activity fuels fumarate accumulation and drives lipid accumulation in steatotic cells. These findings provide new insights into the pathogenesis of hepatic steatosis and may lead to an improved understanding of the metabolic and transcriptional rewiring associated with NAFLD.

scholarly journals Apigenin Alleviates Non-Alcoholic Fatty Liver Disease by Downregulating the NLRP3/NF-κB Signaling Pathway in Mice

2021 ◽  
Author(s):  
Zheng Lu ◽  
Lu Liu ◽  
Shunxin Zhao ◽  
Jiangtao Zhao ◽  
Sujun Li
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Signaling Pathway ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

Abstract Background: Apigenin, a flavone found in several plant foods with various biological properties including anti-inflammatory and other abilities, alleviated non-alcohol fatty liver disease (NAFLD) induced by a high fat diet (HFD) in mice. However, the mechanisms underlying this protection of inflammation and NAFLD has not been known clearly. Methods: Low density lipoprotein receptor-deficient (Ldlr-/-) mice were fed with HFD diet to induce NAFLD model and were treated with apigenin (50 mg/kg/day) for eight weeks. Hepatic lipid accumulation and inflammation in the livers were analyzed and quantified. In vitro experiments, HepG2 cells were stimulated by LPS plus oleic acid (OA) in the absence of presence of apigenin (50μM). Lipid accumulation and the effect of apigenin on NLRP3/NF-κB signaling pathway was investigated.Results: Apigenin administration reduce the weight, plasma lipid levels in Ldlr-/- mice when fed an HFD. Apigenin (50 mg/kg/day) treated mice displayed reduced hepatic lipid accumulation and inflammation in the livers of mice given the HFD diet. Treating the HepG2 cells with apigenin reduced lipid accumulation. And, apigenin also inhibited activation of NLRP3/NF-κB signaling pathway stimulated by OA together with LPS. Conclusions: Our results indicated that apigenin supplementation prevented NAFLD via down-regulating the NLRP3/NF-κB signaling pathway in mice, and suggested apigenin might be a potential therapeutic agent for the prevention of NAFLD.

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