scholarly journals Role of Intestinal LXRα in Regulating Post-prandial Lipid Excursion and Diet-Induced Hypercholesterolemia and Hepatic Lipid Accumulation

2017 ◽  
Vol 8 ◽  
Author(s):  
Tibiábin Benítez-Santana ◽  
Sarah E. Hugo ◽  
Amnon Schlegel
Keyword(s):  
Lipid Accumulation ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

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 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.

scholarly journals MIF-2/D-DT is an atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis

2021 ◽  
Author(s):  
Omar El Bounkari ◽  
Chunfang Zan ◽  
Jonas Wagner ◽  
Elina Bugar ◽  
Priscila Bourilhon ◽  
...  
Keyword(s):  
B Cell ◽  
Lipid Accumulation ◽  
Vascular Inflammation ◽  
Foam Cell Formation ◽  
Hepatic Lipogenesis ◽  
Lesion Formation ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

Atherosclerosis is the underlying cause of cardiovascular diseases (CVDs) such as myocardial infarction and ischemic stroke. It is a lipid-triggered chronic inflammatory condition of the arterial vascular wall that is driven by various inflammatory pathways including atherogenic cytokines and chemokines. D-dopachrome tautomerase (D-DT), also known as macrophage migration inhibitory factor-2 (MIF-2), belongs to the MIF protein family, which is best known for its pathogenic role in a variety of inflammatory and immune conditions including CVDs. While MIF is well known as a promoter of atherogenic processes, MIF-2 has not been studied in atherosclerosis. Here, we investigated atherosclerosis in hyperlipidemic Mif-2-/-Apoe-/- mice and studied the role of MIF-2 in various atherogenic assays in vitro. We found that global Mif-2 deficiency as well as its pharmacological blockade by 4-CPPC protected against atherosclerotic lesion formation and vascular inflammation in models of early and advanced atherogenesis. On cellular level, MIF-2 promoted monocyte migration in 2D and 3D and monocyte arrest on aortic endothelial monolayers, promoted B-cell chemotaxis in vitro and B-cell homing in vivo, and increased macrophage foam cell formation. Dose curves and direct comparison in a 3D migration set-up suggest that MIF-2 may be a more potent chemokine than MIF for monocytes and B cells. We identify CXCR4 as a novel receptor for MIF-2. The evidence relies on a CXCR4 inhibitor, CXCR4 internalization experiments, MIF-2/CXCR4 binding studies by yeast-CXCR4 transformants, and fluorescence spectroscopic titrations with a soluble CXCR4 surrogate. Of note, Mif-2-/- Apoe-/- mice exhibited decreased plasma cholesterol and triglyceride levels, lower body weights, smaller livers, and profoundly reduced hepatic lipid accumulation compared to Apoe-/- mice. Mechanistic experiments in Huh-7 hepatocytes suggest that MIF-2 regulates the expression and activation of sterol-regulatory element binding protein-1 and -2 (SREBP-1, SREBP-2) to induce lipogenic downstream genes such as FASN and LDLR, while it attenuated the activation of the SREBP inhibiting AMPK pathway. Studies using receptor Inhibitors showed that SREBP activation and hepatic lipoprotein uptake by MIF-2 is mediated by both CXCR4 and CD74. Lastly and in line with a combined role of MIF-2 in vascular inflammation and hepatic lipid accumulation, MIF-2 was found to be profoundly upregulated in unstable human carotid plaques, underscoring a critical role for MIF-2 in advanced stages of atherosclerosis. Together, these data identify MIF-2 as a novel atherogenic chemokine and CXCR4 ligand that not only promotes lesion formation and vascular inflammation but also strongly affects hepatic lipogenesis in an SREBP-mediated manner, possibly linking atherosclerosis and hepatic steatosis.

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.

Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: Role of endotoxin

2008 ◽  
Vol 48 (6) ◽  
pp. 983-992 ◽  
Author(s):  
Ina Bergheim ◽  
Synia Weber ◽  
Miriam Vos ◽  
Sigrid Krämer ◽  
Valentina Volynets ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

scholarly journals Palmitate induces fat accumulation via repressing FoxO1-mediated ATGL-dependent lipolysis in HepG2 hepatocytes

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0243938
Author(s):  
Naiqian Zhao ◽  
Huiwen Tan ◽  
Li Wang ◽  
Le Han ◽  
Yanli Cheng ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Target Gene ◽  
Elevated Serum ◽  
Peroxisome Proliferator ◽  
Alcoholic Fatty Liver ◽  
Fat Accumulation ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Forkhead Box

Obesity is closely associated with non-alcoholic fatty liver disease (NAFLD), and elevated serum palmitate is the link between obesity and excessive hepatic lipid accumulation. Forkhead box O-1 (FoxO1) is one of the FoxO family members of transcription factors and can stimulate adipose triglyceride lipase (ATGL) and suppress its inhibitor G0/G1 switch gene 2 (G0S2) expression in the liver. However, previous researches have also shown conflicting results regarding the role of FoxO1 in hepatic lipid accumulation. We therefore examined the role of FoxO1 as a downstream suppressor to palmitate-stimulated hepatic steatosis. Palmitate significantly promoted lipid accumulation but inhibited lipid decomposition in human HepG2 hepatoma cells. Palmitate also significantly reduced FoxO1, ATGL and its activator comparative gene identification-58 (CGI-58) expression but increased peroxisome proliferator-activated receptorγ (PPARγ) and its target gene G0S2 expression. FoxO1 overexpression significantly increased palmitate-inhibited ATGL and CGI-58 expression but reduced palmitate-stimulated PPARγ and its target gene G0S2 expression. FoxO1 overexpression also inhibited lipid accumulation and promoted lipolysis in palmitate-treated hepatocytes. Overall, these results indicate that FoxO1-mediated ATGL-dependent lipolysis may be an effective molecular mechanism in protecting hepatocytes from palmitate-induced fat accumulation.

The role of increased FGF21 in VLDL-TAG secretion and thermogenic gene expression in mice under protein malnutrition

2021 ◽  
Author(s):  
Yori Ozaki-Masuzawa ◽  
Hiroki Kosaka ◽  
Rino Abiru ◽  
Yumiko Toda ◽  
Kota Kawabata ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Lipid Accumulation ◽  
Liver Lipid ◽  
Protective Role ◽  
Protein Malnutrition ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

Abstract Protein malnutrition promotes hepatic lipid accumulation in growing animals. In these animals, fibroblast growth factor 21 (FGF21) rapidly increases in the liver and circulation and plays a protective role in hepatic lipid accumulation. To investigate the mechanism by which FGF21 protects against liver lipid accumulation under protein malnutrition, we determined whether upregulated FGF21 promotes thermogenesis or secretion of very-low-density lipoprotein (VLDL)–triacylglycerol (TAG). The results showed that protein malnutrition decreased VLDL-TAG secretion, but upregulation of FGF21 did not oppose this effect. In addition, protein malnutrition increased expression of the thermogenic gene uncoupling protein 1 in inguinal white adipose and brown adipose tissue in an FGF21-dependent manner. However, surgically removing inguinal white adipose tissue did not affect liver triglyceride levels in protein-malnourished mice. These data suggest that FGF21 stimulates thermogenesis under protein malnutrition, but this is not the causative factor underlying the protective role of FGF21 against liver lipid accumulation.

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