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The Journal of Cell Biology Nov 2021Mitochondrial function is integrated with cellular status through the regulation of opposing mitochondrial fusion and division events. Here we uncover a link between...
Mitochondrial function is integrated with cellular status through the regulation of opposing mitochondrial fusion and division events. Here we uncover a link between mitochondrial dynamics and lipid metabolism by examining the cellular role of mitochondrial carrier homologue 2 (MTCH2). MTCH2 is a modified outer mitochondrial membrane carrier protein implicated in intrinsic cell death and in the in vivo regulation of fatty acid metabolism. Our data indicate that MTCH2 is a selective effector of starvation-induced mitochondrial hyperfusion, a cytoprotective response to nutrient deprivation. We find that MTCH2 stimulates mitochondrial fusion in a manner dependent on the bioactive lipogenesis intermediate lysophosphatidic acid. We propose that MTCH2 monitors flux through the lipogenesis pathway and transmits this information to the mitochondrial fusion machinery to promote mitochondrial elongation, enhanced energy production, and cellular survival under homeostatic and starvation conditions. These findings will help resolve the roles of MTCH2 and mitochondria in tissue-specific lipid metabolism in animals.
Topics: Animals; Apoptosis; COS Cells; Carrier Proteins; Cell Line; Cell Line, Tumor; Chlorocebus aethiops; HCT116 Cells; Humans; Lipid Metabolism; Lipogenesis; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes; Mitochondrial Proteins
PubMed: 34586346
DOI: 10.1083/jcb.202103122 -
Endocrinology Feb 2024
Topics: Cholesterol; Adrenal Glands; Lipogenesis
PubMed: 38500355
DOI: 10.1210/endocr/bqae032 -
The Journal of Endocrinology May 2023Despite the existence of numerous studies supporting a pathological link between fructose consumption and the development of the metabolic syndrome and its sequelae,... (Review)
Review
Despite the existence of numerous studies supporting a pathological link between fructose consumption and the development of the metabolic syndrome and its sequelae, such as non-alcoholic fatty liver disease (NAFLD), this link remains a contentious issue. With this article, we shed a light on the impact of sugar/fructose intake on hepatic de novo lipogenesis (DNL), an outcome parameter known to be dysregulated in subjects with type 2 diabetes and/or NAFLD. In this review, we present findings from human intervention studies using physiological doses of sugar as well as mechanistic animal studies. There is evidence from both human and animal studies that fructose is a more potent inducer of hepatic lipogenesis than glucose. This is most likely due to the liver's prominent physiological role in fructose metabolism, which may be disrupted under pathological conditions by increased hepatic expression of fructolytic and lipogenic enzymes. Increased DNL may not only contribute to ectopic fat deposition (i.e. in the liver), but it may also impair several metabolic processes through DNL-related fatty acids (e.g. beta-cell function, insulin secretion, or insulin sensitivity).
Topics: Animals; Humans; Non-alcoholic Fatty Liver Disease; Fructose; Lipogenesis; Diabetes Mellitus, Type 2; Liver
PubMed: 36753292
DOI: 10.1530/JOE-22-0270 -
The Journal of Clinical Investigation Jun 2020Hepatic de novo lipogenesis is a major contributor to nonalcoholic fatty liver disease (NAFLD). In this issue of the JCI, Liu and Lin et al. identified Slug as an...
Hepatic de novo lipogenesis is a major contributor to nonalcoholic fatty liver disease (NAFLD). In this issue of the JCI, Liu and Lin et al. identified Slug as an epigenetic regulator of lipogenesis. Their findings suggest that Slug is stabilized by insulin signaling, and that it promotes lipogenesis by recruiting the histone demethylase Lsd1 to the fatty acid synthase gene promoter. On the other hand, genetic deletion or acute depletion of Slug, or Lsd1 inhibition, reduced lipogenesis and protected against obesity-associated NAFLD and insulin resistance in mice. This study advances our understanding of how lipogenesis is regulated downstream of insulin signaling in health and disease.
Topics: Animals; Epigenesis, Genetic; Insulin; Insulin Resistance; Lipogenesis; Liver; Mice; Non-alcoholic Fatty Liver Disease
PubMed: 32364539
DOI: 10.1172/JCI137050 -
Molecular Metabolism Sep 2022Resistance to cell death, a protective mechanism for removing damaged cells, is a "Hallmark of Cancer" that is essential for cancer progression. Increasing attention to... (Review)
Review
BACKGROUND
Resistance to cell death, a protective mechanism for removing damaged cells, is a "Hallmark of Cancer" that is essential for cancer progression. Increasing attention to cancer lipid metabolism has revealed a number of pathways that induce cancer cell death.
SCOPE OF REVIEW
We summarize emerging concepts regarding lipid metabolic reprogramming in cancer that is mainly involved in lipid uptake and trafficking, de novo synthesis and esterification, fatty acid synthesis and oxidation, lipogenesis, and lipolysis. During carcinogenesis and progression, continuous metabolic adaptations are co-opted by cancer cells, to maximize their fitness to the ever-changing environmental. Lipid metabolism and the epigenetic modifying enzymes interact in a bidirectional manner which involves regulating cancer cell death. Moreover, lipids in the tumor microenvironment play unique roles beyond metabolic requirements that promote cancer progression. Finally, we posit potential therapeutic strategies targeting lipid metabolism to improve treatment efficacy and survival of cancer patient.
MAJOR CONCLUSIONS
The profound comprehension of past findings, current trends, and future research directions on resistance to cancer cell death will facilitate the development of novel therapeutic strategies targeting the lipid metabolism.
Topics: Cell Death; Humans; Lipid Metabolism; Lipids; Lipogenesis; Neoplasms; Tumor Microenvironment
PubMed: 35714911
DOI: 10.1016/j.molmet.2022.101529 -
Marine Drugs Sep 2020Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease, encompassing a range of conditions caused by lipid deposition within liver cells,...
Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease, encompassing a range of conditions caused by lipid deposition within liver cells, and is also associated with obesity and metabolic diseases. Here, we investigated the protective effects of diphlorethohydroxycarmalol (DPHC), which is a polyphenol isolated from an edible seaweed, , on palmitate-induced lipotoxicity in the liver. DPHC treatment repressed palmitate-induced cytotoxicity, triglyceride content, and lipid accumulation. DPHC prevented palmitate-induced mRNA and protein expression of SREBP (sterol regulatory element-binding protein) 1, C/EBP (CCAAT-enhancer-binding protein) α, ChREBP (carbohydrate-responsive element-binding protein), and FAS (fatty acid synthase). In addition, palmitate treatment reduced the expression levels of phosphorylated AMP-activated protein kinase (AMPK) and sirtuin (SIRT)1 proteins, and DPHC treatment rescued this reduction. Moreover, DPHC protected palmitate-induced liver toxicity and lipogenesis, as well as inflammation, and enhanced AMPK and SIRT1 signaling in zebrafish. These results suggest that DPHC possesses protective effects against palmitate-induced toxicity in the liver by preventing lipogenesis and inflammation. DPHC could be used as a potential therapeutic or preventive agent for fatty liver diseases.
Topics: Hep G2 Cells; Heterocyclic Compounds, 3-Ring; Humans; Inflammation; Lipogenesis; Liver; Non-alcoholic Fatty Liver Disease; Palmitates; Phaeophyceae
PubMed: 32962167
DOI: 10.3390/md18090475 -
Trends in Endocrinology and Metabolism:... Oct 2016Epidemiological studies link fructose consumption with metabolic disease, an association attributable in part to fructose-mediated lipogenesis. The mechanisms governing... (Review)
Review
Epidemiological studies link fructose consumption with metabolic disease, an association attributable in part to fructose-mediated lipogenesis. The mechanisms governing fructose-induced lipogenesis and disease remain debated. Acutely, fructose increases de novo lipogenesis through the efficient and uninhibited action of ketohexokinase and aldolase B which yields substrates for fatty-acid synthesis. Chronic fructose consumption further enhances the capacity for hepatic fructose metabolism by activating several key transcription factors (i.e., SREBP1c and ChREBP) which augment the expression of lipogenic enzymes, increasing lipogenesis and further compounding hypertriglyceridemia and hepatic steatosis. Hepatic insulin resistance develops from diacylglycerol-PKCɛ-mediated impairment of insulin signaling and possibly additional mechanisms. Initiatives that decrease fructose consumption and therapies that block fructose-mediated lipogenesis will be necessary to avert future metabolic pandemics.
Topics: Animals; Fructose; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Lipogenesis; Signal Transduction
PubMed: 27387598
DOI: 10.1016/j.tem.2016.06.005 -
Cold Spring Harbor Symposia on... 2011Circadian rhythms have evolved to anticipate metabolic needs across the 24-h light/dark cycle. This is accomplished by circadian expression of metabolic genes... (Review)
Review
Circadian rhythms have evolved to anticipate metabolic needs across the 24-h light/dark cycle. This is accomplished by circadian expression of metabolic genes orchestrated by transcription factors through chromatin remodeling and histone modifications. Our recent genome-wide study on histone deacetylase 3 (HDAC3) in mouse liver provides novel insights into the molecular link between circadian rhythm and hepatic de novo lipogenesis. We found that liver-specific knockout of HDAC3 in adult mouse displays severe hepatic steatosis associated with enhanced de novo lipogenesis and increased expression of lipogenic genes. Genome-wide analysis (ChIP-seq) revealed a pronounced circadian pattern of HDAC3 occupancy on genes involved in lipid metabolism, which is inversely related to histone acetylation and RNA polymerase II recruitment at these sites. The cistromes of HDAC3 and its binding partner, nuclear receptor corepressor (NCoR), significantly overlap with that of Rev-erbα, a nuclear receptor directly involved in the core circadian machinery. Knockout of Rev-erbα in mouse also leads to hepatic steatosis and enhanced de novo lipogenesis. Collectively, these data suggest that the circadian epigenomic remodeling controlled by HDAC3, and largely directed by Rev-erbα, is essential for homeostasis of the lipogenic process in liver.
Topics: Animals; Chromatin; Circadian Rhythm; Epigenomics; Histone Deacetylases; Humans; Lipogenesis; Liver
PubMed: 21900149
DOI: 10.1101/sqb.2011.76.011494 -
The Journal of Physiology Jul 2019Fructose is a commonly ingested dietary sugar which has been implicated in playing a particularly harmful role in the development of metabolic disease. Fructose is... (Review)
Review
Fructose is a commonly ingested dietary sugar which has been implicated in playing a particularly harmful role in the development of metabolic disease. Fructose is primarily metabolised by the liver in humans, and increases rates of hepatic de novo lipogenesis. Fructose increases hepatic de novo lipogenesis via numerous mechanisms: by altering transcriptional and allosteric regulation, interfering with cellular energy sensing, and disrupting the balance between lipid synthesis and lipid oxidation. Hepatic de novo lipogenesis is also upregulated by the inability to synthesise glycogen, either when storage is inhibited in knock-down animal models or storage is saturated in glycogen storage disease. Considering that fructose has the capacity to upregulate hepatic glycogen storage, and replenish these stores more readily following glycogen depleting exercise, the idea that hepatic glycogen storage and hepatic de novo lipogenesis are linked is an attractive prospect. We propose that hepatic glycogen stores may be a key factor in determining the metabolic responses to fructose ingestion, and saturation of hepatic glycogen stores could exacerbate the negative metabolic effects of excessive fructose intake. Since physical activity potently modulates glycogen metabolism, this provides a rationale for considering nutrient-physical activity interactions in metabolic health.
Topics: Animals; Energy Intake; Exercise; Fructose; Humans; Lipogenesis; Liver; Liver Glycogen
PubMed: 30950506
DOI: 10.1113/JP277767 -
Basic & Clinical Pharmacology &... Sep 2022Somatostatin and its analogues, known as somatostatin receptor ligands (SRLs), have been reported to attenuate weight gain in some clinical settings. However, their...
Somatostatin and its analogues, known as somatostatin receptor ligands (SRLs), have been reported to attenuate weight gain in some clinical settings. However, their direct effects on preadipocytes are barely investigated. Therefore, this study aimed to evaluate the influence of SRLs on preadipocytes and to further explore the potential mechanisms. Cell Counting Kit-8 assay, Oil Red O staining, triglyceride contents measurements, quantitative polymerase chain reaction (qPCR) and western blot were used to investigate the effects of SRLs on preadipocytes. We found that three SRLs (octreotide, TT232 and pasireotide) inhibited cell viability after 8-48 h but not 4 h. Further western blot results showed that they significantly suppressed activation of PI3K/Akt pathway. Besides, lipid accumulation was also significantly inhibited by these SRLs. Moreover, mRNA levels of some critical adipogenic markers, including Pparg, Cebpa, Fasn, Fabp4, Acaca and Lpl, were downregulated by the treatments of all these SRLs. Consistently, the protein expression of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα) and fatty acid synthase (FAS) was also suppressed by SRLs. SRLs inhibit the proliferation and lipogenesis in preadipocytes. Their inhibitory effects on cell proliferation may be mediated by the downregulated PI3K/Akt pathway, and the suppressive actions on lipogenesis may be related to the decreased PPARγ and C/EBPα expression.
Topics: 3T3-L1 Cells; Adipocytes; Animals; CCAAT-Enhancer-Binding Protein-alpha; Cell Differentiation; Cell Proliferation; Ligands; Lipogenesis; Mice; PPAR gamma; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptors, Somatostatin; Somatostatin
PubMed: 35688794
DOI: 10.1111/bcpt.13762