scholarly journals Moderate Calorie Restriction Enhances Hepatic Glucagon Sensitivity in Aged Mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 685-685
Author(s):  
Stephen Hutchison ◽  
Anastasiia Vasileva ◽  
Tyler Marx ◽  
Samantha Slavin ◽  
Jennifer Stern
Keyword(s):  
Calorie Restriction ◽  
Lipid Accumulation ◽  
Receptor Expression ◽  
Metabolic Function ◽  
Ampk Activation ◽  
Glucagon Receptor ◽  
Hepatic Lipid ◽  
Aged Mice ◽  
Hepatic Lipid Accumulation

Abstract Chronic calorie restriction (CR) without malnutrition delays the onset of aging, extends lifespan, and improves metabolic function in many species. These CR-induced benefits have largely concentrated on the role of insulin signaling, while ignoring its counter-regulatory hormone, glucagon. Like insulin, hyperglucagonemia and decreased glucagon sensitivity are associated with impaired glucose homeostasis and decreased longevity. Conversely, activation of target molecules downstream of glucagon signaling such as AMPK and FGF21 are known to ameliorate these age-related impairments in metabolic function. To investigate the potential role of glucagon receptor signaling in CR-induced improvements in aging, we have implemented a moderate 15% CR in the mouse. Our studies show that a 15% calorie restriction initiated at 4 months of age enhances hypoglycemia-stimulated glucagon secretion (P<.01) and decreases basal serum glucagon (P<.01), while having no effect on glucagon receptor expression at the liver in 26-month-old mice. Consistent with enhanced hepatic glucagon sensitivity, CR increases glucagon-stimulated hepatic cyclic AMP production (P<.05). Glucagon is a primary regulator of AMPK activation and FGF21 release, both of which have been proposed as key molecules to account for CR-induced benefits to aging. CR increases both hepatic AMPK activation (P<.05) and FGF21 mRNA expression (P<.05). Additionally, CR reduces hepatic lipid accumulation (P<.05), and decreases fasting respiratory quotient (P<.001), indicating an increase in lipid oxidation. Our studies demonstrate that a moderate (15%) CR regimen enhances glucagon sensitivity and decreases hepatic lipid accumulation in aged mice. Thus, we propose glucagon signaling as a mediator of CR-induced improvements in aging.

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.

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