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13 pages, 24856 KiB

Open AccessCommunication

The Novel Inhibitory Effect of YM976 on Adipocyte Differentiation

by Hee Jung Kim, Dong-Hoon Kim and Sung Hee Um

Cells 2023, 12(2), 205; https://doi.org/10.3390/cells12020205 - 4 Jan 2023

Cited by 3 | Viewed by 2493

Abstract

The pyrimidine derivative YM976 (4-(3-chlorophenyl)-1,7-diethylpyrido(2,3-d)-pyrimidin-2(1H)-one) exerts anti-inflammatory and anti-asthmatic effects. Considering that accumulation of lipids in adipose tissue is accompanied by inflammation, we investigated whether YM976 affects adipocyte differentiation. We found that YM976 significantly decreased lipid accumulation without cytotoxicity [...] Read more.

The pyrimidine derivative YM976 (4-(3-chlorophenyl)-1,7-diethylpyrido(2,3-d)-pyrimidin-2(1H)-one) exerts anti-inflammatory and anti-asthmatic effects. Considering that accumulation of lipids in adipose tissue is accompanied by inflammation, we investigated whether YM976 affects adipocyte differentiation. We found that YM976 significantly decreased lipid accumulation without cytotoxicity and reduced the expression levels of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα) as well as their lipogenic regulators including fatty acid synthase (FASN) and fatty acid-binding protein 4 (FABP4) in 3T3-L1 cells induced for differentiation. YM976 mainly inhibited the early stage of adipocyte differentiation. Furthermore, intracellular cAMP level was elevated by YM976 resulting in increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Conversely, decreasing the levels of AMPK or treatment with Compound C, an AMPK inhibitor, lessened the suppressive effects of YM976 on PPARγ transcriptional activity and adipogenesis. Thus, our results suggest YM976 as a novel potential compound for controlling lipid accumulation and formation of adipocytes in obesity. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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31 pages, 5010 KiB

Open AccessArticle

Fat Quality Impacts the Effect of a High-Fat Diet on the Fatty Acid Profile, Life History Traits and Gene Expression in Drosophila melanogaster

by Virginia Eickelberg, Gerald Rimbach, Yvonne Seidler, Mario Hasler, Stefanie Staats and Kai Lüersen

Cells 2022, 11(24), 4043; https://doi.org/10.3390/cells11244043 - 14 Dec 2022

Cited by 5 | Viewed by 3187

Abstract

Feeding a high-fat diet (HFD) has been shown to alter phenotypic and metabolic parameters in Drosophila melanogaster. However, the impact of fat quantity and quality remains uncertain. We first used butterfat (BF) as an example to investigate the effects of increasing dietary [...] Read more.

Feeding a high-fat diet (HFD) has been shown to alter phenotypic and metabolic parameters in Drosophila melanogaster. However, the impact of fat quantity and quality remains uncertain. We first used butterfat (BF) as an example to investigate the effects of increasing dietary fat content (3–12%) on male and female fruit flies. Although body weight and body composition were not altered by any BF concentration, health parameters, such as lifespan, fecundity and larval development, were negatively affected in a dose-dependent manner. When fruit flies were fed various 12% HFDs (BF, sunflower oil, olive oil, linseed oil, fish oil), their fatty acid profiles shifted according to the dietary fat qualities. Moreover, fat quality was found to determine the effect size of the response to an HFD for traits, such as lifespan, climbing activity, or fertility. Consistently, we also found a highly fat quality-specific transcriptional response to three exemplary HFD qualities with a small overlap of only 30 differentially expressed genes associated with the immune/stress response and fatty acid metabolism. In conclusion, our data indicate that not only the fat content but also the fat quality is a crucial factor in terms of life-history traits when applying an HFD in D. melanogaster. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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19 pages, 4261 KiB

Open AccessArticle

Dietary Choline Mitigates High-Fat Diet-Impaired Chylomicrons Assembly via UPRer Modulated by perk DNA Methylation

by Zhen-Yu Bai, Hua Zheng, Zhi Luo, Christer Hogstrand, Ling-Jiao Wang and Yu-Feng Song

Cells 2022, 11(23), 3848; https://doi.org/10.3390/cells11233848 - 30 Nov 2022

Cited by 4 | Viewed by 2122

Abstract

High-fat diets (HFD) lead to impairment of chylomicrons (CMs) assembly and adversely influence intestinal lipid homeostasis. However, the mechanisms of HFD impairing CMs assembly have yet to be fully understood. Additionally, although choline, as a lipid-lowering agent, has been widely used and its [...] Read more.

High-fat diets (HFD) lead to impairment of chylomicrons (CMs) assembly and adversely influence intestinal lipid homeostasis. However, the mechanisms of HFD impairing CMs assembly have yet to be fully understood. Additionally, although choline, as a lipid-lowering agent, has been widely used and its deficiency has been closely linked to non-alcoholic steatohepatitis (NASH), the contribution of choline by functioning as a methyl donor in alleviating HFD-induced intestinal lipid deposition is unknown. Thus, this study was conducted to determine the mechanism of HFD impairing CMs assembly and also tested the effect of choline acting as a methyl donor in this process. To this end, in this study, four diets (control, HFD, choline and HFD + choline diet) were fed to yellow catfish for 10 weeks in vivo and their intestinal epithelial cells were isolated and incubated for 36 h in fatty acids (FA) with or without choline solution combining si-perk transfection in vitro. The key findings from this study as follows: (1) HFD caused impairment of CMs assembly main by unfolded protein response (UPRer). HFD activated perk and then induced UPRer, which led to endoplasmic reticulum dysfunction and further impaired CMs assembly via protein–protein interactions between Perk and Apob48. (2) Choline inhibited the transcriptional expression level of perk via activating the −211 CpG methylation site, which initiated the subsequent ameliorating effect on HFD-impaired CMs assembly and intestinal lipid dysfunction. These results provide a new insight into direct crosstalk between UPRer and CMs assembly, and also emphasize the critical contribution of choline acting as a methyl donor and shed new light on choline-deficient diet-induced NASH. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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19 pages, 4510 KiB

Open AccessFeature PaperArticle

AIBP Regulates Metabolism of Ketone and Lipids but Not Mitochondrial Respiration

by Jun-dae Kim, Teng Zhou, Aijun Zhang, Shumin Li, Anisha A. Gupte, Dale J. Hamilton and Longhou Fang

Cells 2022, 11(22), 3643; https://doi.org/10.3390/cells11223643 - 17 Nov 2022

Cited by 1 | Viewed by 2432

Abstract

Accumulating evidence indicates that the APOA1 binding protein (AIBP)—a secreted protein—plays a profound role in lipid metabolism. Interestingly, AIBP also functions as an NAD(P)H-hydrate epimerase to catalyze the interconversion of NAD(P)H hydrate [NAD(P)HX] epimers and is renamed as NAXE. Thus, we call it [...] Read more.

Accumulating evidence indicates that the APOA1 binding protein (AIBP)—a secreted protein—plays a profound role in lipid metabolism. Interestingly, AIBP also functions as an NAD(P)H-hydrate epimerase to catalyze the interconversion of NAD(P)H hydrate [NAD(P)HX] epimers and is renamed as NAXE. Thus, we call it NAXE hereafter. We investigated its role in NAD(P)H-involved metabolism in murine cardiomyocytes, focusing on the metabolism of hexose, lipids, and amino acids as well as mitochondrial redox function. Unbiased metabolite profiling of cardiac tissue shows that NAXE knockout markedly upregulates the ketone body 3-hydroxybutyric acid (3-HB) and increases or trends increasing lipid-associated metabolites cholesterol, α-linolenic acid and deoxycholic acid. Paralleling greater ketone levels, ChemRICH analysis of the NAXE-regulated metabolites shows reduced abundance of hexose despite similar glucose levels in control and NAXE-deficient blood. NAXE knockout reduces cardiac lactic acid but has no effect on the content of other NAD(P)H-regulated metabolites, including those associated with glucose metabolism, the pentose phosphate pathway, or Krebs cycle flux. Although NAXE is present in mitochondria, it has no apparent effect on mitochondrial oxidative phosphorylation. Instead, we detected more metabolites that can potentially improve cardiac function (3-HB, adenosine, and α-linolenic acid) in the Naxe^−/− heart; these mice also perform better in aerobic exercise. Our data reveal a new role of NAXE in cardiac ketone and lipid metabolism. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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13 pages, 4918 KiB

Open AccessArticle

MiR-23b Promotes Porcine Preadipocyte Differentiation via SESN3 and ACSL4

by Meng Li, Na Zhang, Jiao Li, Wanfeng Zhang, Wei Hei, Mengting Ji, Yang Yang, Guoqing Cao, Xiaohong Guo and Bugao Li

Cells 2022, 11(15), 2339; https://doi.org/10.3390/cells11152339 - 29 Jul 2022

Cited by 7 | Viewed by 2220

Abstract

Genetic improvement of pork quality is one of the hot topics in pig germplasm innovation. Backfat thickness and intramuscular fat content are important indexes of meat quality. MiRNAs are becoming recognized as a crucial regulator of adipose development. Therefore, it is crucial to [...] Read more.

Genetic improvement of pork quality is one of the hot topics in pig germplasm innovation. Backfat thickness and intramuscular fat content are important indexes of meat quality. MiRNAs are becoming recognized as a crucial regulator of adipose development. Therefore, it is crucial to understand how miR-23b regulates fat metabolism at the molecular level. In the present study, Oil Red O staining, and Western blot were used to evaluate the effect of miR-23b on the differentiation of porcine preadipocytes. Dual-luciferase reporter gene assay, pulldown, and RIP were used to reveal the mechanism of miR-23b regulating cell differentiation. The findings demonstrated that miR-23b promotes the expression of adipogenic factors and increases the content of lipid droplets, thus promoting the differentiation of preadipocytes. Further research found that miR-23b can directly bind to the 3’UTR of SESN3 to regulate adipogenic differentiation. In addition, it was speculated that miR-23b controls cell differentiation by positively regulating the expression of ACSL4 in other ways. Here, we demonstrate that miR-23b promotes the differentiation of porcine preadipocytes by targeting SESN3 and promoting the expression of ACSL4. The present study is meaningful to the improvement of pork quality and the development of animal husbandry. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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Review

Jump to: Research

20 pages, 2000 KiB

Open AccessReview

Targeting Liver X Receptors for the Treatment of Non-Alcoholic Fatty Liver Disease

by Hyejin Kim, Chaewon Park and Tae Hyun Kim

Cells 2023, 12(9), 1292; https://doi.org/10.3390/cells12091292 - 1 May 2023

Cited by 6 | Viewed by 4151

Abstract

Non-alcoholic fatty liver disease (NAFLD) refers to a range of conditions in which excess lipids accumulate in the liver, possibly leading to serious hepatic manifestations such as steatohepatitis, fibrosis/cirrhosis and cancer. Despite its increasing prevalence and significant impact on liver disease-associated mortality worldwide, [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) refers to a range of conditions in which excess lipids accumulate in the liver, possibly leading to serious hepatic manifestations such as steatohepatitis, fibrosis/cirrhosis and cancer. Despite its increasing prevalence and significant impact on liver disease-associated mortality worldwide, no medication has been approved for the treatment of NAFLD yet. Liver X receptors α/β (LXRα and LXRβ) are lipid-activated nuclear receptors that serve as master regulators of lipid homeostasis and play pivotal roles in controlling various metabolic processes, including lipid metabolism, inflammation and immune response. Of note, NAFLD progression is characterized by increased accumulation of triglycerides and cholesterol, hepatic de novo lipogenesis, mitochondrial dysfunction and augmented inflammation, all of which are highly attributed to dysregulated LXR signaling. Thus, targeting LXRs may provide promising strategies for the treatment of NAFLD. However, emerging evidence has revealed that modulating the activity of LXRs has various metabolic consequences, as the main functions of LXRs can distinctively vary in a cell type-dependent manner. Therefore, understanding how LXRs in the liver integrate various signaling pathways and regulate metabolic homeostasis from a cellular perspective using recent advances in research may provide new insights into therapeutic strategies for NAFLD and associated metabolic diseases. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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12 pages, 1114 KiB

Open AccessReview

Polyunsaturated Fatty Acids Drive Lipid Peroxidation during Ferroptosis

by Michael S. Mortensen, Jimena Ruiz and Jennifer L. Watts

Cells 2023, 12(5), 804; https://doi.org/10.3390/cells12050804 - 4 Mar 2023

Cited by 56 | Viewed by 7764

Abstract

Ferroptosis is a form of regulated cell death that is intricately linked to cellular metabolism. In the forefront of research on ferroptosis, the peroxidation of polyunsaturated fatty acids has emerged as a key driver of oxidative damage to cellular membranes leading to cell [...] Read more.

Ferroptosis is a form of regulated cell death that is intricately linked to cellular metabolism. In the forefront of research on ferroptosis, the peroxidation of polyunsaturated fatty acids has emerged as a key driver of oxidative damage to cellular membranes leading to cell death. Here, we review the involvement of polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs), lipid remodeling enzymes and lipid peroxidation in ferroptosis, highlighting studies revealing how using the multicellular model organism Caenorhabditis elegans contributes to the understanding of the roles of specific lipids and lipid mediators in ferroptosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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24 pages, 1125 KiB

Open AccessReview

Cellular and Molecular Control of Lipid Metabolism in Idiopathic Pulmonary Fibrosis: Clinical Application of the Lysophosphatidic Acid Pathway

by Yusuke Nakamura and Yasuo Shimizu

Cells 2023, 12(4), 548; https://doi.org/10.3390/cells12040548 - 8 Feb 2023

Cited by 7 | Viewed by 4157

Abstract

Idiopathic pulmonary fibrosis (IPF) is a representative disease that causes fibrosis of the lungs. Its pathogenesis is thought to be characterized by sustained injury to alveolar epithelial cells and the resultant abnormal tissue repair, but it has not been fully elucidated. IPF is [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is a representative disease that causes fibrosis of the lungs. Its pathogenesis is thought to be characterized by sustained injury to alveolar epithelial cells and the resultant abnormal tissue repair, but it has not been fully elucidated. IPF is currently difficult to cure and is known to follow a chronic progressive course, with the patient’s survival period estimated at about three years. The disease occasionally exacerbates acutely, leading to a fatal outcome. In recent years, it has become evident that lipid metabolism is involved in the fibrosis of lungs, and various reports have been made at the cellular level as well as at the organic level. The balance among eicosanoids, sphingolipids, and lipid composition has been reported to be involved in fibrosis, with particularly close attention being paid to a bioactive lipid “lysophosphatidic acid (LPA)” and its pathway. LPA signals are found in a wide variety of cells, including alveolar epithelial cells, vascular endothelial cells, and fibroblasts, and have been reported to intensify pulmonary fibrosis via LPA receptors. For instance, in alveolar epithelial cells, LPA signals reportedly induce mitochondrial dysfunction, leading to epithelial damage, or induce the transcription of profibrotic cytokines. Based on these mechanisms, LPA receptor inhibitors and the metabolic enzymes involved in LPA formation are now considered targets for developing novel means of IPF treatment. Advances in basic research on the relationships between fibrosis and lipid metabolism are opening the path to new therapies targeting lipid metabolism in the treatment of IPF. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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30 pages, 2535 KiB

Open AccessReview

Detoxification Cytochrome P450s (CYPs) in Families 1–3 Produce Functional Oxylipins from Polyunsaturated Fatty Acids

by Jazmine A. Eccles and William S. Baldwin

Cells 2023, 12(1), 82; https://doi.org/10.3390/cells12010082 - 24 Dec 2022

Cited by 9 | Viewed by 3082

Abstract

This manuscript reviews the CYP-mediated production of oxylipins and the current known function of these diverse set of oxylipins with emphasis on the detoxification CYPs in families 1–3. Our knowledge of oxylipin function has greatly increased over the past 3–7 years with new [...] Read more.

This manuscript reviews the CYP-mediated production of oxylipins and the current known function of these diverse set of oxylipins with emphasis on the detoxification CYPs in families 1–3. Our knowledge of oxylipin function has greatly increased over the past 3–7 years with new theories on stability and function. This includes a significant amount of new information on oxylipins produced from linoleic acid (LA) and the omega-3 PUFA-derived oxylipins such as α-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). However, there is still a lack of knowledge regarding the primary CYP responsible for producing specific oxylipins, and a lack of mechanistic insight for some clinical associations between outcomes and oxylipin levels. In addition, the role of CYPs in the production of oxylipins as signaling molecules for obesity, energy utilization, and development have increased greatly with potential interactions between diet, endocrinology, and pharmacology/toxicology due to nuclear receptor mediated CYP induction, CYP inhibition, and receptor interactions/crosstalk. The potential for diet-diet and diet-drug/chemical interactions is high given that these promiscuous CYPs metabolize a plethora of different endogenous and exogenous chemicals. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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