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Diabetologia May 2023Non-alcoholic fatty liver disease (NAFLD) associated with type 2 diabetes may more easily progress towards severe forms of non-alcoholic steatohepatitis (NASH) and...
AIMS/HYPOTHESIS
Non-alcoholic fatty liver disease (NAFLD) associated with type 2 diabetes may more easily progress towards severe forms of non-alcoholic steatohepatitis (NASH) and cirrhosis. Although the Wnt effector transcription factor 7-like 2 (TCF7L2) is closely associated with type 2 diabetes risk, the role of TCF7L2 in NAFLD development remains unclear. Here, we investigated how changes in TCF7L2 expression in the liver affects hepatic lipid metabolism based on the major risk factors of NAFLD development.
METHODS
Tcf7l2 was selectively ablated in the liver of C57BL/6N mice by inducing the albumin (Alb) promoter to recombine Tcf7l2 alleles floxed at exon 5 (liver-specific Tcf7l2-knockout [KO] mice: Alb-Cre;Tcf7l2). Alb-Cre;Tcf7l2 and their wild-type (Tcf7l2) littermates were fed a high-fat diet (HFD) or a high-carbohydrate diet (HCD) for 22 weeks to reproduce NAFLD/NASH. Mice were refed a standard chow diet or an HCD to stimulate de novo lipogenesis (DNL) or fed an HFD to provide exogenous fatty acids. We analysed glucose and insulin sensitivity, metabolic respiration, mRNA expression profiles, hepatic triglyceride (TG), hepatic DNL, selected hepatic metabolites, selected plasma metabolites and liver histology.
RESULTS
Alb-Cre;Tcf7l2 essentially exhibited increased lipogenic genes, but there were no changes in hepatic lipid content in mice fed a normal chow diet. However, following 22 weeks of diet-induced NAFLD/NASH conditions, liver steatosis was exacerbated owing to preferential metabolism of carbohydrate over fat. Indeed, hepatic Tcf7l2 deficiency enhanced liver lipid content in a manner that was dependent on the duration and amount of exposure to carbohydrates, owing to cell-autonomous increases in hepatic DNL. Mechanistically, TCF7L2 regulated the transcriptional activity of Mlxipl (also known as ChREBP) by modulating O-GlcNAcylation and protein content of carbohydrate response element binding protein (ChREBP), and targeted Srebf1 (also called SREBP1) via miRNA (miR)-33-5p in hepatocytes. Eventually, restoring TCF7L2 expression at the physiological level in the liver of Alb-Cre;Tcf7l2 mice alleviated liver steatosis without altering body composition under both acute and chronic HCD conditions.
CONCLUSIONS/INTERPRETATION
In mice, loss of hepatic Tcf7l2 contributes to liver steatosis by inducing preferential metabolism of carbohydrates via DNL activation. Therefore, TCF7L2 could be a promising regulator of the NAFLD associated with high-carbohydrate diets and diabetes since TCF7L2 deficiency may lead to development of NAFLD by promoting utilisation of excess glucose pools through activating DNL.
DATA AVAILABILITY
RNA-sequencing data have been deposited into the NCBI GEO under the accession number GSE162449 ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162449 ).
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2; Lipogenesis; Mice, Inbred C57BL; Liver; Hepatocytes; Diet, High-Fat; Triglycerides; Glucose; Transcription Factor 7-Like 2 Protein
PubMed: 36759348
DOI: 10.1007/s00125-023-05878-8 -
Developmental Cell Mar 2022Tissues and cells require fuel and cellular building blocks to respond to proliferative cues. In this issue of Developmental Cell, Vaidyanathan and colleagues modulate...
Tissues and cells require fuel and cellular building blocks to respond to proliferative cues. In this issue of Developmental Cell, Vaidyanathan and colleagues modulate yes-associated protein (YAP) signaling and its downstream targets, together with phenotyping and metabolic tracing, to determine the central role of YAP in lipogenesis and associated liver growth.
Topics: Cell Proliferation; Lipogenesis; Mechanistic Target of Rapamycin Complex 1; Sterol Regulatory Element Binding Protein 1; YAP-Signaling Proteins
PubMed: 35349794
DOI: 10.1016/j.devcel.2022.03.003 -
Pharmacology & Therapeutics May 2023Obesity is a key risk factor for the development of metabolic disease. Bioactive sphingolipid metabolites are among the lipids increased in obesity. Obesogenic saturated... (Review)
Review
Obesity is a key risk factor for the development of metabolic disease. Bioactive sphingolipid metabolites are among the lipids increased in obesity. Obesogenic saturated fatty acids are substrates for serine palmitoyltransferase (SPT) the rate-limiting step in de novo sphingolipid biosynthesis. The mammalian orosomucoid-like protein isoforms ORMDL1-3 negatively regulate SPT activity. Here we summarize evidence that dysregulation of sphingolipid metabolism and SPT activity correlates with pathogenesis of obesity. This review also discusses the current understanding of the function of SPT and ORMDL in obesity and metabolic disease. Gaps and limitations in current knowledge are highlighted together with the need to further understand how ORMDL3, which has been identified as an obesity-related gene, contributes to the pathogenesis of obesity and development of metabolic disease related to its physiological functions. Finally, we point out the needs to move this young field of research forward.
Topics: Animals; Humans; Membrane Proteins; Sphingolipids; Lipid Metabolism; Lipogenesis; Mammals
PubMed: 37003301
DOI: 10.1016/j.pharmthera.2023.108401 -
International Journal of Molecular... May 2021Glioblastoma (GBM) is an extremely aggressive tumor originating from neural stem cells of the central nervous system, which has high histopathological and genomic... (Review)
Review
Glioblastoma (GBM) is an extremely aggressive tumor originating from neural stem cells of the central nervous system, which has high histopathological and genomic diversity. Mitochondria are cellular organelles associated with the regulation of cellular metabolism, redox signaling, energy generation, regulation of cell proliferation, and apoptosis. Accumulation of mutations in mitochondrial DNA (mtDNA) leads to mitochondrial dysfunction that plays an important role in GBM pathogenesis, favoring abnormal energy and reactive oxygen species production and resistance to apoptosis and to chemotherapeutic agents. The present review summarizes the known mitochondrial DNA alterations related to GBM, their cellular and metabolic consequences, and their association with diagnosis, prognosis, and treatment.
Topics: Cell Line, Tumor; DNA, Mitochondrial; Energy Metabolism; Genetic Variation; Genome, Mitochondrial; Genomics; Glioblastoma; Humans; Lipogenesis; Mitochondria; Mutation
PubMed: 34072607
DOI: 10.3390/ijms22115855 -
International Journal of Molecular... Jan 2022Metabolic-associated fatty liver disease (MAFLD), which is often linked to obesity, encompasses a large spectrum of hepatic lesions, including simple fatty liver,... (Review)
Review
Metabolic-associated fatty liver disease (MAFLD), which is often linked to obesity, encompasses a large spectrum of hepatic lesions, including simple fatty liver, steatohepatitis, cirrhosis and hepatocellular carcinoma. Besides nutritional and genetic factors, different xenobiotics such as pharmaceuticals and environmental toxicants are suspected to aggravate MAFLD in obese individuals. More specifically, pre-existing fatty liver or steatohepatitis may worsen, or fatty liver may progress faster to steatohepatitis in treated patients, or exposed individuals. The mechanisms whereby xenobiotics can aggravate MAFLD are still poorly understood and are currently under deep investigations. Nevertheless, previous studies pointed to the role of different metabolic pathways and cellular events such as activation of de novo lipogenesis and mitochondrial dysfunction, mostly associated with reactive oxygen species overproduction. This review presents the available data gathered with some prototypic compounds with a focus on corticosteroids and rosiglitazone for pharmaceuticals as well as bisphenol A and perfluorooctanoic acid for endocrine disruptors. Although not typically considered as a xenobiotic, ethanol is also discussed because its abuse has dire consequences on obese liver.
Topics: Humans; Lipogenesis; Liver; Non-alcoholic Fatty Liver Disease; Obesity; Xenobiotics
PubMed: 35162986
DOI: 10.3390/ijms23031062 -
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 -
Nutrients Aug 2020Macroalgae have attracted great interest for their potential applications in nutraceutical and pharmaceutical industries as source of bioactive medicinal products and... (Review)
Review
Macroalgae have attracted great interest for their potential applications in nutraceutical and pharmaceutical industries as source of bioactive medicinal products and food ingredients. This review gathers data from and studies addressing the anti-obesity effects of macroalgae. Great consensus exists in all reported studies concerning the reduction induced by seaweed extracts in the expression of transcriptional factors controlling adipogenesis. In animals, macroalgae reduced body fat accumulation and prevented other obesity features, such as dyslipidemia, insulin resistance and fatty liver. These effects are not due to food intake reduction, since few studies have reported such event. Indeed, the effects on metabolic pathways in target tissues/organs seem to play a more relevant role. Macroalgae can reduce de novo lipogenesis, limiting fatty acid availability for triglyceride synthesis in white adipose tissue. This effect has been observed in both cell cultures and adipose tissue from animals treated with macroalgae extracts. In addition, increased fatty acid oxidation and thermogenic capacity, as well as a shift towards healthier gut microbiota composition may contribute to the body fat-lowering effect of macroalgae. Studies in humans are needed to determine whether macroalgae can represent a feasible tool to prevent and/or manage overweight and obesity.
Topics: Adipogenesis; Adipose Tissue, White; Animals; Anti-Obesity Agents; Fatty Acids; Lipogenesis; Liver; Obesity; Oxidation-Reduction; Plant Extracts; Seaweed; Thermogenesis
PubMed: 32784488
DOI: 10.3390/nu12082378 -
Nature Communications Apr 2023Cancer cells exhibit elevated lipid synthesis. In breast and other cancer types, genes involved in lipid production are highly upregulated, but the mechanisms that...
Cancer cells exhibit elevated lipid synthesis. In breast and other cancer types, genes involved in lipid production are highly upregulated, but the mechanisms that control their expression remain poorly understood. Using integrated transcriptomic, lipidomic, and molecular studies, here we report that DAXX is a regulator of oncogenic lipogenesis. DAXX depletion attenuates, while its overexpression enhances, lipogenic gene expression, lipogenesis, and tumor growth. Mechanistically, DAXX interacts with SREBP1 and SREBP2 and activates SREBP-mediated transcription. DAXX associates with lipogenic gene promoters through SREBPs. Underscoring the critical roles for the DAXX-SREBP interaction for lipogenesis, SREBP2 knockdown attenuates tumor growth in cells with DAXX overexpression, and DAXX mutants unable to bind SREBP1/2 have weakened activity in promoting lipogenesis and tumor growth. Remarkably, a DAXX mutant deficient of SUMO-binding fails to activate SREBP1/2 and lipogenesis due to impaired SREBP binding and chromatin recruitment and is defective of stimulating tumorigenesis. Hence, DAXX's SUMO-binding activity is critical to oncogenic lipogenesis. Notably, a peptide corresponding to DAXX's C-terminal SUMO-interacting motif (SIM2) is cell-membrane permeable, disrupts the DAXX-SREBP1/2 interactions, and inhibits lipogenesis and tumor growth. These results establish DAXX as a regulator of lipogenesis and a potential therapeutic target for cancer therapy.
Topics: Carcinogenesis; Cell Transformation, Neoplastic; Co-Repressor Proteins; Lipids; Lipogenesis; Molecular Chaperones; Neoplasms; Sterol Regulatory Element Binding Protein 1; Animals; Mice
PubMed: 37045819
DOI: 10.1038/s41467-023-37501-0 -
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 -
Alcoholism, Clinical and Experimental... Apr 2020Endocannabinoids are lipid mediators that interact with the same cannabinoid receptors that recognize Δ -tetrahydrocannabinol (THC), the psychoactive constituent of... (Review)
Review
Endocannabinoids are lipid mediators that interact with the same cannabinoid receptors that recognize Δ -tetrahydrocannabinol (THC), the psychoactive constituent of marijuana, to induce similar effects in the brain and periphery. Alcohol and THC are both addictive substances whose acute use elicits rewarding effects that can lead to chronic and compulsive use via engaging similar signaling pathways in the brain. In the liver, both alcohol and endocannabinoids activate lipogenic gene expression leading to fatty liver disease. This review focuses on evidence accumulated over the last 2 decades to indicate that both the addictive neural effects of ethanol and its organ toxic effects in the liver and elsewhere are mediated, to a large extent, by endocannabinoids signaling via cannabinoid-1 receptors (CB R). The therapeutic potential of CB R blockade globally or in peripheral tissues only is also discussed.
Topics: Alcohol Drinking; Alcoholism; Animals; Binge Drinking; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Endocannabinoids; Ethanol; Humans; Lipogenesis; Liver; Liver Diseases, Alcoholic; Marijuana Abuse; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2
PubMed: 32056226
DOI: 10.1111/acer.14306