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Theranostics 2020The functions of fibrinogen-like protein 2 (fgl2) have been studied in many inflammatory and neoplastic diseases, but the role of fgl2 in nonalcoholic fatty liver...
Fibrinogen-like protein 2 aggravates nonalcoholic steatohepatitis via interaction with TLR4, eliciting inflammation in macrophages and inducing hepatic lipid metabolism disorder.
The functions of fibrinogen-like protein 2 (fgl2) have been studied in many inflammatory and neoplastic diseases, but the role of fgl2 in nonalcoholic fatty liver disease has not yet been elucidated. In this study, we sought to investigate the role of fgl2 in the pathogenesis of nonalcoholic steatohepatitis (NASH). Hepatic fgl2 expression was tested in patients with nonalcoholic fatty liver (NAFL) or NASH and controls. Wild-type and fgl2-/- C57BL/6 mice were subjected to a methionine/choline-deficient (MCD) diet or a high-fat diet (HFD) to establish NASH models. Bone marrow-derived macrophages (BMDMs) stimulated with LPS or free fatty acids were used for the study. In both humans and mice with NASH, macrophage accumulation was concomitant with significantly increased fgl2 expression in the liver. Fgl2 deficiency attenuated liver steatosis and inflammation in diet-induced murine models of NASH. In both liver tissues and BMDMs from NASH mice, fgl2 deficiency resulted in reduced levels of proinflammatory cytokines and reactive oxygen species (ROS) compared with levels in wild-type controls. Activation of NF-κB, p38-MAPK and NLRP3 inflammasomes was also suppressed upon fgl2 disruption. Moreover, lipogenic genes (Fasn and SREBP-2) were downregulated while lipolytic genes (PPAR and CPT1A) were upregulated in the livers of fgl2-/- NASH mice. Primary hepatocytes incubated with the medium collected from fgl2-/- BMDMs showed less fat deposition than those incubated with WT BMDMs. Furthermore, we discovered that fgl2 combined with TLR4 mediates the activation of the Myd88-dependent signaling pathway, which may contribute to inflammation and lipid metabolism disorders. These data suggest that fgl2 aggravates the progression of NASH through activation of NF-κB, p38-MAPK and NLRP3 inflammasomes in macrophages, which consequently induces overproduction of proinflammatory cytokines and lipid metabolism disorders. An interaction of fgl2 and TLR4 may in part contribute to the activation of inflammatory signaling pathways in macrophages.
Topics: Animals; Cytokines; Diet, High-Fat; Fibrinogen; Hepatocytes; Humans; Inflammation; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Liver; Liver Cirrhosis; Macrophages; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Non-alcoholic Fatty Liver Disease; Reactive Oxygen Species; Signal Transduction; Toll-Like Receptor 4
PubMed: 32863955
DOI: 10.7150/thno.44297 -
Frontiers in Endocrinology 2021Adipose tissue (e.g. white, brown and brite) plays a critical role in modulating energy metabolism. Activating brown adipose tissue (BAT) and inducing browning in white...
BACKGROUND
Adipose tissue (e.g. white, brown and brite) plays a critical role in modulating energy metabolism. Activating brown adipose tissue (BAT) and inducing browning in white adipose tissue (WAT) has been proposed to be a potential molecular target for obesity treatment. Emodin is a natural anthraquinone derivative that exhibits variety of pharmacologic effects including lowering lipids and regulating glucose utilization. However, the underlying mechanism of action is still unclear. In the present study, we investigated whether emodin could alleviate obesity promoting browning process in adipose tissue.
METHODS
C57BL/6J mice were fed with high fat diet to induce obesity. Emodin at the doses of 40 and 80 mg/kg were orally given to obesity mice for consecutive 6 weeks. Parameters including fasting blood glucose, oral glucose tolerance, blood lipids, and the ratios of subcutaneous white adipose tissue (scWAT) or BAT mass to body weight, and morphology of adipose tissue were observed. Besides, the protein expression of uncoupling protein 1 (UCP1) and prohibitin in BAT and scWAT was determined by immunohistochemistry method. Relative mRNA expression of , transmembrane protein 26 () and in scWAT was analyzed using qRT-PCR. And the protein expression of UCP1, CD36, fatty acid transporter 4 (FATP4), peroxisome proliferator-activated receptor alpha (PPARα) and prohibitin of scWAT and BAT were analyzed using western blotting. In addition, ultra-high-performance liquid chromatography with electrospray ionization tandem mass spectrometry was utilized to detect the small lipid metabolites of scWAT and BAT.
RESULTS
Emodin decreased the body weight and food intake in HFD-induced obesity mice, and it also improved the glucose tolerance and reduced the blood lipids. Emodin treatment induced beiging of WAT, and more multilocular lipid droplets were found in scWAT. Also, emodin significantly increased markers of beige adipocytes, e.g. , and mRNA in scWAT, and UCP1, CD36, FATP4, PPARα and prohibitin protein expression in scWAT and BAT. Furthermore, emodin perturbed the lipidomic profiles in scWAT and BAT of obese mice. Emodin increased total ceramides (Cers), lysophosphatidylcholines (LPCs), lyso-phosphatidylcholines oxygen (LPCs-O), and phosphatidylethanolamines oxygen (PEs-O) species concentration in scWAT. Specifically, emodin significantly up-regulated levels of Cer (34:1), LPC (18:2), LPC-(O-20:2), PC (O-40:7), PE (O-36:3), PE (O-38:6), PE (O-40:6), and sphingolipid (41:0) [SM (41:0)], and down-regulated PC (O-38:0), PE (O-40:4), PE (O-40:5) in scWAT of obesity mice. In terms of lipid matabolites of BAT, the emodin remarkably increased the total PCs levels, which was driven by significant increase of PC (30:0), PC (32:1), PC (32:2), PC (33:4) and PC (38:0) species. In addition, it also increased species of LPCs, e.g. LPC (20:0), LPC (20:1), LPC (22:0), LPC (22:1), LPC (24:0), and LPC (24:1). Especially, emodin treatment could reverse the ratio of PC/PE in HFD-induced obese mice.
CONCLUSIONS
These results indicated that emodin could ameliorate adiposity and improve metabolic disorders in obese mice. Also, emodin could promote browning in scWAT and activate the BAT activities. In addition, emodin treatment-induced changes to the scWAT and BAT lipidome were highly specific to certain molecular lipid species, indicating that changes in tissue lipid content reflects selective remodeling in scWAT and BAT of both glycerophospholipids and sphingolipids in response to emodin treatment.
Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Body Weight; Diet, High-Fat; Emodin; Lipid Metabolism; Lipid Metabolism Disorders; Male; Mice; Mice, Obese; Obesity; Thermogenesis
PubMed: 34040579
DOI: 10.3389/fendo.2021.618037 -
Environment International Aug 2023Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous environmental contaminants with well-documented hepatotoxicity. However, the mechanistic linkage...
BACKGROUND
Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous environmental contaminants with well-documented hepatotoxicity. However, the mechanistic linkage between PFAS exposure and non-alcoholic fatty liver disease (NAFLD) remains largely elusive.
OBJECTIVES
This study aimed to explore PFAS-to-NAFLD link and the relevant molecular mechanisms.
METHODS
The cross-sectional analyses using National Health and Nutrition Examination Survey (NHANES) data were conducted to investigate the association between PFAS exposure and NAFLD. A combination of in silico toxicological analyses, bioinformatics approaches, animal experiments, and in vitro assays was used to explore the molecular initiating events (MIEs) and key events (KEs) in PFAS-induced hepatic lipid metabolism disorders.
RESULTS
The cross-sectional analyses with NHANES data revealed the significant association between PFAS exposure and hepatic steatosis/NAFLD. The in silico toxicological analyses showed that PPARα activation induced by perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), prototypical representatives of PFAS, is the critical MIE associated with NAFLD-predominant liver diseases. Transcriptome-based bioinformatic annotation and analyses identified that transcriptional upregulation of hepatic acyl-CoA oxidase 1 (ACOX1) in PPARα-regulated peroxisomal β-oxidation pathway was the KE involved with PFOA/PFOS-perturbed hepatic lipid metabolic pathways in humans, mice and rats. The in vivo and in vitro assays further verified that ACOX1-mediated oxidative stress contributed to mitochondrial compromise and lipid accumulation in PFOA/PFOS-exposed mouse hepatocytes, which could be mitigated by co-treatment with ACOX1 inhibitor and mitochondria ROS scavenger. Additionally, we observed that besides PFOA and PFOS, hepatic ACOX1 exhibited good-fit response to short-term exposures of long-chain (C7-C10) perfluoroalkyl carboxylic acids (PFHpA, PFNA, PFDA) and perfluoroalkyl sulfonic acids (PFHpS, PFDS) in human hepatocyte spheroids through benchmark dose (BMD) modeling.
CONCLUSION
Our study unveils a novel molecular target for PFAS-induced hepatic lipid metabolic disorders, shedding new light on prediction, assessment, and mitigation of PFAS hepatotoxicity.
Topics: Humans; Mice; Rats; Animals; Non-alcoholic Fatty Liver Disease; PPAR alpha; Nutrition Surveys; Lipid Metabolism; Cross-Sectional Studies; Alkanesulfonic Acids; Caprylates; Lipid Metabolism Disorders; Fluorocarbons; Chemical and Drug Induced Liver Injury; Environmental Pollutants
PubMed: 37572494
DOI: 10.1016/j.envint.2023.108138 -
Pediatric Annals Mar 2021Current scientific evidence has proven that atherosclerosis is a process that begins in childhood and tracks into adulthood, likely culminating in adverse cardiovascular...
Current scientific evidence has proven that atherosclerosis is a process that begins in childhood and tracks into adulthood, likely culminating in adverse cardiovascular events such as coronary artery disease, peripheral artery disease, and stroke. In addition, the obesity epidemic and increasing awareness of genetic lipid disorders has made the understanding and management of lipid disorders necessary for pediatricians. Childhood offers a unique opportunity for preventing, modifying, or eliminating risk factors and, in doing so, reversing or slowing the process of atherosclerosis. In general, management involves targeted lifestyle interventions such as strict dietary changes and increases in physical activity. In some circumstances, pharmacotherapy, even in childhood, is warranted. .
Topics: Atherosclerosis; Child; Diet; Exercise; Humans; Life Style; Lipid Metabolism Disorders; Mass Screening; Metabolic Syndrome; Obesity; Pediatrics; Risk Factors
PubMed: 34038650
DOI: 10.3928/19382359-20210218-01 -
Nutrients Mar 2013Hypertriglyceridemia (HTG) is commonly encountered in lipid and cardiology clinics. Severe HTG warrants treatment because of the associated increased risk of acute...
Hypertriglyceridemia (HTG) is commonly encountered in lipid and cardiology clinics. Severe HTG warrants treatment because of the associated increased risk of acute pancreatitis. However, the need to treat, and the correct treatment approach for patients with mild to moderate HTG are issues for ongoing evaluation. In the past, it was felt that triglyceride does not directly contribute to development of atherosclerotic plaques. However, this view is evolving, especially for triglyceride-related fractions and variables measured in the non-fasting state. Our understanding of the etiology, genetics and classification of HTG states is also evolving. Previously, HTG was considered to be a dominant disorder associated with variation within a single gene. The old nomenclature includes the term "familial" in the names of several hyperlipoproteinemia (HLP) phenotypes that included HTG as part of their profile, including combined hyperlipidemia (HLP type 2B), dysbetalipoproteinemia (HLP type 3), simple HTG (HLP type 4) and mixed hyperlipidemia (HLP type 5). This old thinking has given way to the idea that genetic susceptibility to HTG results from cumulative effects of multiple genetic variants acting in concert. HTG most is often a "polygenic" or "multigenic" trait. However, a few rare autosomal recessive forms of severe HTG have been defined. Treatment depends on the overall clinical context, including severity of HTG, concomitant presence of other lipid disturbances, and the patient's global risk of cardiovascular disease. Therapeutic strategies include dietary counselling, lifestyle management, control of secondary factors, use of omega-3 preparations and selective use of pharmaceutical agents.
Topics: Adult; Fatty Acids, Omega-3; Genetic Predisposition to Disease; Genetic Variation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertriglyceridemia; Hypolipidemic Agents
PubMed: 23525082
DOI: 10.3390/nu5030981 -
Reviews in Cardiovascular Medicine Sep 2021Atherosclerosis ranks first among cardiovascular system diseases. It is the "disease of the century", and more than 50% of people with circulatory pathology die of it.... (Review)
Review
Atherosclerosis ranks first among cardiovascular system diseases. It is the "disease of the century", and more than 50% of people with circulatory pathology die of it. The clinical manifestation of atherosclerosis is observed at the middle and older ages, but it is known that the pathological process develops much earlier. There has been a clear trend in theoretical and practical cardiology in recent years to study the earliest atherogenic markers. Epidemiological, clinical, and morphological studies have proved the presence in children and adolescents of sexual, endogenous, exogenous, primary, and potentiating risk factors contributing to an early formation of a pathogenic foundation for atherosclerotic cardiovascular diseases. Disorders of lipid metabolism - dyslipidemias are attributed to the most significant risk factor for atherosclerotic cardiovascular diseases. The DLP prevalence in the pediatric population is extremely high. According to the results of conducted global studies, lipid metabolism disorders occur in more than 70% of children and adolescents. It causes the need for timely diagnostic, therapeutic and preventive measures. The need to extrapolate the risk factor concept to childhood age is justified by several reasons, the main of which include the broadest spread of atherosclerosis that has become a global pandemic, genetic determinism, and low variability of the lipid spectrum of blood serum: the levels of lipids and lipoproteins discovered in childhood are stable throughout life and have an independent prognostic value. That is why the most practical significance is inherent to the study of lipid and lipoprotein metabolism, starting in the early periods of lipid and lipoprotein ontogenesis. Since risk factors can be identified at the preclinical stage of the atherosclerotic process, dyslipidemia phenotyping will facilitate identifying children and adolescents at risk of developing cardiovascular pathologies in the future. The study objective is to examine the pathophysiological aspects of lipid and lipoprotein metabolism and examine DLP epidemiology - as the leading atherosclerotic cardiovascular disease risk factor in children and adolescents, DLP classification, modern approaches to DLP diagnosis and management.
Topics: Adolescent; Aged; Atherosclerosis; Cardiovascular Diseases; Child; Dyslipidemias; Humans; Lipids; Middle Aged; Pediatricians; Risk Factors
PubMed: 34565080
DOI: 10.31083/j.rcm2203088 -
Journal of Atherosclerosis and... Aug 2021Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as sitosterol. This disease is caused by loss-of-function... (Review)
Review
Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as sitosterol. This disease is caused by loss-of-function genetic mutations in ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively), both of which play important roles in selective excretion of plant sterols from the liver and intestine, leading to failure to prevent absorption of food plant sterols. This disorder has been considered to be extremely rare. However, accumulated clinical data as well as genetics suggest the possibility of a much higher prevalence. Its clinical manifestations resemble those observed in patients with familial hypercholesterolemia (FH), including tendon xanthomas, hyper LDL-cholesterolemia, and premature coronary atherosclerosis. We provide an overview of this recessive genetic disease, diagnostic as well as therapeutic tips, and the latest diagnostic criteria in Japan.
Topics: Disease Management; Humans; Hypercholesterolemia; Intestinal Diseases; Japan; Lipid Metabolism, Inborn Errors; Phytosterols
PubMed: 33907061
DOI: 10.5551/jat.RV17052 -
Endocrinology and Metabolism Clinics of... Sep 2022Most endocrine disorders are chronic in nature, and thus even a minor effect to increase risk for cardiovascular disease can lead to a significant impact over prolonged... (Review)
Review
Most endocrine disorders are chronic in nature, and thus even a minor effect to increase risk for cardiovascular disease can lead to a significant impact over prolonged duration. Although robust therapies exist for many endocrine disorders (eg suppression of excess hormone amounts, or replacement of hormone deficiencies), the therapies do not perfectly restore normal physiology. Thus, individuals with endocrine disorders are at potential increased cardiovascular disease risk, and maximizing strategies to reduce that risk are needed. This article reviews various endocrine conditions that can impact lipid levels and/or cardiovascular disease risk.
Topics: Cardiovascular Diseases; Dyslipidemias; Endocrine System Diseases; Hormones; Humans
PubMed: 35963630
DOI: 10.1016/j.ecl.2022.02.003 -
Biomedicine & Pharmacotherapy =... Oct 2023Lipid metabolism is a complex process that maintains the normal physiological function of the human body. The disorder of lipid metabolism has been implicated in various... (Review)
Review
Lipid metabolism is a complex process that maintains the normal physiological function of the human body. The disorder of lipid metabolism has been implicated in various human diseases, such as cardiovascular diseases and bone diseases. Intervertebral disc degeneration (IDD), an age-related degenerative disease in the musculoskeletal system, is characterized by high morbidity, high treatment cost, and chronic recurrence. Lipid metabolism disorder may promote the pathogenesis of IDD, and the potential mechanisms are complex. Leptin, resistin, nicotinamide phosphoribosyltransferase (NAMPT), fatty acids, and cholesterol may promote the pathogenesis of IDD, while lipocalin, adiponectin, and progranulin (PGRN) exhibit protective activity against IDD development. Lipid metabolism disorder contributes to extracellular matrix (ECM) degradation, cell apoptosis, and cartilage calcification in the intervertebral discs (IVDs) by activating inflammatory responses, endoplasmic reticulum (ER) stress, and oxidative stress and inhibiting autophagy. Several lines of agents have been developed to target lipid metabolism disorder. Inhibition of lipid metabolism disorder may be an effective strategy for the therapeutic management of IDD. However, an in-depth understanding of the molecular mechanism of lipid metabolism disorder in promoting IDD development is still needed.
Topics: Humans; Intervertebral Disc Degeneration; Lipid Metabolism; Lipid Metabolism Disorders; Adiponectin; Apoptosis
PubMed: 37651799
DOI: 10.1016/j.biopha.2023.115401 -
International Journal of Molecular... Aug 2020This review discusses how lipophagy and cytosolic lipolysis degrade cellular lipids, as well as how these pathway ys communicate, how they affect lipid metabolism and... (Review)
Review
This review discusses how lipophagy and cytosolic lipolysis degrade cellular lipids, as well as how these pathway ys communicate, how they affect lipid metabolism and energy homeostasis in cells and how their dysfunction affects the pathogenesis of lipid storage and lipid metabolism diseases. Answers to these questions will likely uncover novel strategies for the treatment of aforementioned human diseases, but, above all, will avoid destructive effects of high concentrations of lipids-referred to as lipotoxicity-resulting in cellular dysfunction and cell death.
Topics: Animals; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Energy Metabolism; Homeostasis; Humans; Lipid Metabolism; Lipid Metabolism Disorders; Lipolysis; Mechanistic Target of Rapamycin Complex 1; Signal Transduction
PubMed: 32854299
DOI: 10.3390/ijms21176113