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.

scholarly journals Mechanism of the Inhibitory Effects ofEucommia ulmoidesOliv. Cortex Extracts (EUCE) in the CCl4-Induced Acute Liver Lipid Accumulation in Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Chang-Feng Jin ◽  
Bo Li ◽  
Shun-Mei Lin ◽  
Raj-Kumar Yadav ◽  
Hyung-Ryong Kim ◽  
...  
Keyword(s):  
Er Stress ◽  
Lipid Accumulation ◽  
Liver Lipid ◽  
Eucommia Ulmoides ◽  
Dependent Manner ◽  
Protective Effects ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Er Stress Response ◽  
Acute Injection

Eucommia ulmoidesOliv. (EU) has been used for treatment of liver diseases. The protective effects ofEucommia UlmoidesOliv. cortex extracts (EUCE) on the carbon tetrachloride- (CCl4-) induced hepatic lipid accumulation were examined in this study. Rats were orally treated with EUCE in different doses prior to an intraperitoneal injection of 1 mg/kg CCl4. Acute injection of CCl4decreased plasma triglyceride but increased hepatic triglyceride and cholesterol as compared to control rats. On the other hand, the pretreatment with EUCE diminished these effects at a dose-dependent manner. CCl4treatment decreased glutathione (GSH) and increased malondialdehyde (MDA) accompanied by activated P450 2E1. The pretreatment with EUCE significantly improved these deleterious effects of CCl4. CCl4treatment increased P450 2E1 activation and ApoB accumulation. Pretreatment with EUCE reversed these effects. ER stress response was significantly increased by CCl4, which was inhibited by EUCE. One of the possible ER stress regulatory mechanisms, lysosomal activity, was examined. CCl4reduced lysosomal enzymes that were reversed with the EUCE. The results indicate that oral pretreatment with EUCE may protect liver against CCl4-induced hepatic lipid accumulation. ER stress and its related ROS regulation are suggested as a possible mechanism in the antidyslipidemic effect of EUCE.

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.

Abstract 540: Activation of Srebp1c Processing is Required in Flx-Induced Hepatic Lipid Accumulation

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Jing Xiong
Keyword(s):  
Lipid Accumulation ◽  
Proteolytic Cleavage ◽  
Mild Stress ◽  
Dependent Manner ◽  
Proteolytic Activation ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Primary Mouse ◽  
Mouse Hepatocytes ◽  
Liver Tissues

Fluoxetine (FLX), a typical drug belonging to the category of selective serotonin reuptake inhibitors (SSRI), is the most widely prescribed psychoactive drug in the treatment of depression and other mood disorders. It has been demonstrated that the administration of FLX increases the possibility of weight gain and dyslipidemia. We find previously that dysregulation of lipogenic and lipolytic genes is critical in FLX-promoted hepatic lipid accumulation. Therefore, a chronic mild stress depression model and cultured primary mouse hepatocytes were used to investigate the effects and underlying mechanisms of FLX on the promoted hepatic lipid accumulation. The evidence have shown that FLX increases the concentrations of triglyceride (TG) and total cholesterol (TC) in the liver tissues of depressive mice, while only increases TG in the liver tissues of normal mice. FLX induces lipid accumulation in both normal and depressive mice by upregulating the lipogeneic genes Acetyl-CoA carboxylase 1 (ACC1) and Fatty acid synthase (FAS) expression and downregulating the lipolytic genes carboxylesterase 1 (CES1) and CES2. Using primary cultured mouse hepatocytes, it is shown that FLX promotes the expression of transcription factor SREBP1c as well as its proteolytic cleavage and nuclear translocation. FLX significantly suppresses SREBP1c proteolytic cleavage in hepatocytes after the incubation lasting as short as 3 hours, which is a more prompt way than the elevated expression of SREBP1c. Further experiments show that the specific inhibitors of proteases S1P and S2P attenuate FLX-induced SREBP1c activation and hepatic lipid accumulation. As SCAP (SREBP cleavage-activating protein) escorts SREBPs from the endoplasmic reticulum to the Golgi complex where proteases cleave SREBPs and therefore is required for SREBP activation, we find that FLX promotes the protein level of SCAP in a concentration- and time-dependent manner. In conclusion, FLX directly acts on the hepatocytes by facilitating the expression and proteolytic activation of SREBP1c to promote hepatic lipid accumulation. The findings not only provide new insight into the understanding of the mechanisms for SSRI-mediated dyslipidemia effects, but also suggest a novel therapeutic target to interfere.

scholarly journals t10,c12-CLA decreases adiposity in peripubertal mice without dose-related detrimental effects on mammary development, inflammation status, and metabolism

2010 ◽  
Vol 299 (6) ◽  
pp. R1521-R1528 ◽  
Author(s):  
M. R. Foote ◽  
S. L. Giesy ◽  
G. Bernal-Santos ◽  
D. E. Bauman ◽  
Y. R. Boisclair
Keyword(s):  
Lipid Accumulation ◽  
Inflammatory Responses ◽  
Mouse Mammary Gland ◽  
Mammary Development ◽  
Dependent Manner ◽  
Negative Effects ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Ductal Hyperplasia ◽  
Igf Binding

The trans 10, cis 12-conjugated linoleic acid (10,12-CLA) isomer reduces adiposity in several animal models. In the mouse, however, this effect is associated with adipose tissue inflammation, hyperinsulinemia and hepatic lipid accumulation. Moreover, 10,12-CLA was recently shown to promote mammary ductal hyperplasia and ErbB2/Her2-driven mammary cancer in the mouse. Reasons for detrimental effects of 10,12-CLA on the mouse mammary gland could relate to its effect on the mammary fat pad (MFP), which is essential for normal development. Accordingly, we hypothesized that mammary effects of 10,12-CLA were mediated through the MFP in a dose-dependent manner. Female FVB mice were fed 10,12-CLA at doses of 0%, 0.1%, 0.2%, or 0.5% of the diet from day 24 of age, and effects on mammary development and metabolism were measured on day 49. The 0.5% dose reduced ductal elongation and caused premature alveolar budding. These effects were associated with increased expression of inflammatory markers and genes shown to alter epithelial growth (IGF binding protein-5) and alveolar budding (TNF-α and receptor of activated NF-κB ligand). The 0.5% dose also caused hyperinsulinemia and hepatic lipid accumulation. In contrast, the 0.1% 10,12-CLA dose had no adverse effects on mammary development, metabolic events, and inflammatory responses, but remained effective in decreasing adipose weights and lipogenic gene expression. These results show that a low dose of 10,12 -CLA reduces adiposity in the mouse without negative effects on mammary development, inflammation, and metabolism, and suggest that previously reported detrimental effects relate to the use of excessive doses.

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.

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