-
Molecules (Basel, Switzerland) Aug 2021Bacteria belonging to the genus are frequent components of microbial communities in diverse natural environments. Some rhodococcal species exhibit the outstanding... (Review)
Review
Bacteria belonging to the genus are frequent components of microbial communities in diverse natural environments. Some rhodococcal species exhibit the outstanding ability to produce significant amounts of triacylglycerols (TAG) (>20% of cellular dry weight) in the presence of an excess of the carbon source and limitation of the nitrogen source. For this reason, they can be considered as oleaginous microorganisms. As occurs as well in eukaryotic single-cell oil (SCO) producers, these bacteria possess specific physiological properties and molecular mechanisms that differentiate them from other microorganisms unable to synthesize TAG. In this review, we summarized several of the well-characterized molecular mechanisms that enable oleaginous rhodococci to produce significant amounts of SCO. Furthermore, we highlighted the ability of these microorganisms to degrade a wide range of carbon sources coupled to lipogenesis. The qualitative and quantitative oil production by rhodococci from diverse industrial wastes has also been included. Finally, we summarized the genetic and metabolic approaches applied to oleaginous rhodococci to improve SCO production. This review provides a comprehensive and integrating vision on the potential of oleaginous rhodococci to be considered as microbial biofactories for microbial oil production.
Topics: Biofuels; Carbon; Lipogenesis; Oils; Phylogeny; Rhodococcus
PubMed: 34443455
DOI: 10.3390/molecules26164871 -
Seminars in Liver Disease Feb 2022Metabolic rewiring is one of the hallmarks of cancer. Altered de novo lipogenesis is one of the pivotal metabolic events deregulated in cancers. Sterol regulatory...
Metabolic rewiring is one of the hallmarks of cancer. Altered de novo lipogenesis is one of the pivotal metabolic events deregulated in cancers. Sterol regulatory element-binding transcription factor 1 (SREBP1) controls the transcription of major enzymes involved in de novo lipogenesis, including ACLY, ACACA, FASN, and SCD. Studies have shown the increased de novo lipogenesis in human hepatocellular carcinoma (HCC) samples. Multiple mechanisms, such as activation of the AKT/mechanistic target of rapamycin (mTOR) pathway, lead to high SREBP1 induction and the coordinated enhanced expression of , , and genes. Subsequent functional analyses have unraveled these enzymes' critical role(s) and the related de novo lipogenesis in hepatocarcinogenesis. Importantly, targeting these molecules might be a promising strategy for HCC treatment. This paper comprehensively summarizes de novo lipogenesis rewiring in HCC and how this pathway might be therapeutically targeted.
Topics: Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Humans; Lipogenesis; Liver Neoplasms
PubMed: 34311471
DOI: 10.1055/s-0041-1731709 -
Diabetes & Metabolism Journal Sep 2021Nonalcoholic fatty liver disease (NAFLD) is a major public health problem and the most common form of chronic liver disease, affecting 25% of the global population.... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) is a major public health problem and the most common form of chronic liver disease, affecting 25% of the global population. Although NAFLD is closely linked with obesity, insulin resistance, and type 2 diabetes mellitus, knowledge on its pathogenesis remains incomplete. Emerging data have underscored the importance of Rho-kinase (Rho-associated coiled-coil-containing kinase [ROCK]) action in the maintenance of normal hepatic lipid homeostasis. In particular, pharmacological blockade of ROCK in hepatocytes or hepatic stellate cells prevents the progression of liver diseases such as NAFLD and fibrosis. Moreover, mice lacking hepatic ROCK1 are protected against obesity-induced fatty liver diseases by suppressing hepatic de novo lipogenesis. Here we review the roles of ROCK as an indispensable regulator of obesity-induced fatty liver disease and highlight the key cellular pathway governing hepatic lipid accumulation, with focus on de novo lipogenesis and its impact on therapeutic potential. Consequently, a comprehensive understanding of the metabolic milieu linking to liver dysfunction triggered by ROCK activation may help identify new targets for treating fatty liver diseases such as NAFLD.
Topics: Animals; Diabetes Mellitus, Type 2; Lipogenesis; Mice; Non-alcoholic Fatty Liver Disease; rho-Associated Kinases
PubMed: 34610720
DOI: 10.4093/dmj.2021.0197 -
Diabetes Jul 2021Wnt signaling is an ancient and evolutionarily conserved pathway with fundamental roles in the development of adipose tissues. Roles of this pathway in mesenchymal stem... (Review)
Review
Wnt signaling is an ancient and evolutionarily conserved pathway with fundamental roles in the development of adipose tissues. Roles of this pathway in mesenchymal stem cell fate determination and differentiation have been extensively studied. Indeed, canonical Wnt signaling is a significant endogenous inhibitor of adipogenesis and promoter of other cell fates, including osteogenesis, chondrogenesis, and myogenesis. However, emerging genetic evidence in both humans and mice suggests central roles for Wnt signaling in body fat distribution, obesity, and metabolic dysfunction. Herein, we highlight recent studies that have begun to unravel the contributions of various Wnt pathway members to critical adipocyte functions, including carbohydrate and lipid metabolism. We further explore compelling evidence of complex and coordinated interactions between adipocytes and other cell types within adipose tissues, including stromal, immune, and endothelial cells. Given the evolutionary conservation and ubiquitous cellular distribution of this pathway, uncovering the contributions of Wnt signaling to cell metabolism has exciting implications for therapeutic intervention in widespread pathologic states, including obesity, diabetes, and cancers.
Topics: Adipocytes; Adipogenesis; Animals; Humans; Lipogenesis; Mesenchymal Stem Cells; Metabolic Diseases; Mice; Osteoblasts; Transcription Factor 7-Like 2 Protein; Wnt Signaling Pathway; beta Catenin
PubMed: 34155042
DOI: 10.2337/dbi20-0015 -
International Journal of Environmental... Mar 2021In recent years, lipid metabolism has gained greater attention in several diseases including cancer. Dysregulation of fatty acid metabolism is a key component in breast... (Review)
Review
In recent years, lipid metabolism has gained greater attention in several diseases including cancer. Dysregulation of fatty acid metabolism is a key component in breast cancer malignant transformation. In particular, de novo lipogenesis provides the substrate required by the proliferating tumor cells to maintain their membrane composition and energetic functions during enhanced growth. However, it appears that not all breast cancer subtypes depend on de novo lipogenesis for fatty acid replenishment. Indeed, while breast cancer luminal subtypes rely on de novo lipogenesis, the basal-like receptor-negative subtype overexpresses genes involved in the utilization of exogenous-derived fatty acids, in the synthesis of triacylglycerols and lipid droplets, and fatty acid oxidation. These metabolic differences are specifically associated with genomic and proteomic changes that can perturb lipogenic enzymes and related pathways. This behavior is further supported by the observation that breast cancer patients can be stratified according to their molecular profiles. Moreover, the discovery that extracellular vesicles act as a vehicle of metabolic enzymes and oncometabolites may provide the opportunity to noninvasively define tumor metabolic signature. Here, we focus on de novo lipogenesis and the specific differences exhibited by breast cancer subtypes and examine the functional contribution of lipogenic enzymes and associated transcription factors in the regulation of tumorigenic processes.
Topics: Breast Neoplasms; Fatty Acids; Humans; Lipid Metabolism; Lipogenesis; Proteomics
PubMed: 33808259
DOI: 10.3390/ijerph18073575 -
Diabetologia Jul 2023PPARGC1A encodes peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), a central regulator of energy metabolism and mitochondrial function. A common...
AIMS/HYPOTHESIS
PPARGC1A encodes peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), a central regulator of energy metabolism and mitochondrial function. A common polymorphism in PPARGC1A (rs8192678, C/T, Gly482Ser) has been associated with obesity and related metabolic disorders, but no published functional studies have investigated direct allele-specific effects in adipocyte biology. We examined whether rs8192678 is a causal variant and reveal its biological function in human white adipose cells.
METHODS
We used CRISPR-Cas9 genome editing to perform an allelic switch (C-to-T or T-to-C) at rs8192678 in an isogenic human pre-adipocyte white adipose tissue (hWAs) cell line. Allele-edited single-cell clones were expanded and screened to obtain homozygous T/T (Ser482Ser), C/C (Gly482Gly) and heterozygous C/T (Gly482Ser) isogenic cell populations, followed by functional studies of the allele-dependent effects on white adipocyte differentiation and mitochondrial function.
RESULTS
After differentiation, the C/C adipocytes were visibly less BODIPY-positive than T/T and C/T adipocytes, and had significantly lower triacylglycerol content. The C allele presented a dose-dependent lowering effect on lipogenesis, as well as lower expression of genes critical for adipogenesis, lipid catabolism, lipogenesis and lipolysis. Moreover, C/C adipocytes had decreased oxygen consumption rate (OCR) at basal and maximal respiration, and lower ATP-linked OCR. We determined that these effects were a consequence of a C-allele-driven dysregulation of PGC-1α protein content, turnover rate and transcriptional coactivator activity.
CONCLUSIONS/INTERPRETATION
Our data show allele-specific causal effects of the rs8192678 variant on adipogenic differentiation. The C allele confers lower levels of PPARGC1A mRNA and PGC-1α protein, as well as disrupted dynamics of PGC-1α turnover and activity, with downstream effects on cellular differentiation and mitochondrial function. Our study provides the first experimentally deduced insights on the effects of rs8192678 on adipocyte phenotype.
Topics: Humans; Alleles; Lipogenesis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Adipocytes, White; Cell Differentiation
PubMed: 37171500
DOI: 10.1007/s00125-023-05915-6 -
Biochemical Society Transactions Oct 2015The protein tribbles-1, encoded by the gene TRIB1, is increasingly recognized as a major regulator of multiple cellular and physiological processes in humans. Recent... (Review)
Review
The protein tribbles-1, encoded by the gene TRIB1, is increasingly recognized as a major regulator of multiple cellular and physiological processes in humans. Recent human genetic studies, as well as molecular biological approaches, have implicated this intriguing protein in the aetiology of multiple human diseases, including myeloid leukaemia, Crohn's disease, non-alcoholic fatty liver disease (NAFLD), dyslipidaemia and coronary artery disease (CAD). Genome-wide association studies (GWAS) have repeatedly identified variants at the genomic TRIB1 locus as being significantly associated with multiple plasma lipid traits and cardiovascular disease (CVD) in humans. The involvement of TRIB1 in hepatic lipid metabolism has been validated through viral-mediated hepatic overexpression of the gene in mice; increasing levels of TRIB1 decreased plasma lipids in a dose-dependent manner. Additional studies have implicated TRIB1 in the regulation of hepatic lipogenesis and NAFLD. The exact mechanisms of TRIB1 regulation of both plasma lipids and hepatic lipogenesis remain undetermined, although multiple signalling pathways and transcription factors have been implicated in tribbles-1 function. Recent reports have been aimed at developing TRIB1-based lipid therapeutics. In summary, tribbles-1 is an important modulator of human energy metabolism and metabolic syndromes and worthy of future studies aimed at investigating its potential as a therapeutic target.
Topics: Cardiovascular Diseases; Genome-Wide Association Study; Humans; Intracellular Signaling Peptides and Proteins; Lipid Metabolism; Lipids; Lipogenesis; Liver; Models, Biological; Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 26517927
DOI: 10.1042/BST20150101 -
Diabetes Jul 2016Adipose tissue (AT) regulates systemic insulin sensitivity through multiple mechanisms, and alterations in de novo lipogenesis appear to contribute. Mice overexpressing... (Review)
Review
Adipose tissue (AT) regulates systemic insulin sensitivity through multiple mechanisms, and alterations in de novo lipogenesis appear to contribute. Mice overexpressing GLUT4 in adipocytes (AG4OX) have elevated AT lipogenesis and enhanced glucose tolerance despite being obese and having elevated circulating fatty acids. Lipidomic analysis of AT identified a structurally unique class of lipids, branched fatty acid esters of hydroxy-fatty acids (FAHFAs), which were elevated in AT and serum of AG4OX mice. Palmitic acid esters of hydroxy-stearic acids (PAHSAs) are among the most upregulated FAHFA families in AG4OX mice. Eight PAHSA isomers are present in mouse and human tissues. PAHSA levels are reduced in insulin resistant people, and levels correlate highly with insulin sensitivity. PAHSAs have beneficial metabolic effects. Treatment of obese mice with PAHSAs lowers glycemia and improves glucose tolerance while stimulating glucagon-like peptide 1 and insulin secretion. PAHSAs also reduce inflammatory cytokine production from immune cells and ameliorate adipose inflammation in obesity. PAHSA isomer concentrations are altered in physiological and pathophysiological conditions in a tissue- and isomer-specific manner. The mechanisms most likely involve changes in PAHSA biosynthesis, degradation, and secretion. The discovery of PAHSAs reveals the existence of previously unknown endogenous lipids and biochemical pathways involved in metabolism and inflammation, two fundamental physiological processes.
Topics: Adipocytes; Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Glucose Transporter Type 4; Humans; Lipogenesis; Mice; Obesity; Rats
PubMed: 27288004
DOI: 10.2337/db16-0221 -
Cell Metabolism Aug 2017With the identification of ChREBP in 2001, our interest in understanding the molecular control of carbohydrate sensing has surged. While ChREBP was initially studied as... (Review)
Review
With the identification of ChREBP in 2001, our interest in understanding the molecular control of carbohydrate sensing has surged. While ChREBP was initially studied as a master regulator of lipogenesis in liver and fat tissue, it is now clear that ChREBP functions as a central metabolic coordinator in a variety of cell types in response to environmental and hormonal signals, with wide implications in health and disease. Celebrating its sweet sixteenth birthday, we review here the current knowledge about the function and regulation of ChREBP throughout usual and less explored tissues, to recapitulate ChREBP's role as a whole-body glucose sensor.
Topics: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Glucose; Humans; Lipogenesis; Liver
PubMed: 28768172
DOI: 10.1016/j.cmet.2017.07.004 -
PloS One 2022This study aimed to evaluate relationships among maternal residual feed intake (RFI) with growth performance and expression of genes involved in lipid metabolism in...
This study aimed to evaluate relationships among maternal residual feed intake (RFI) with growth performance and expression of genes involved in lipid metabolism in offspring of Nellore cattle. Fifty-three cows classified as negative or positive RFI by genomic prediction were exposed to fixed-time artificial insemination (FTAI) protocols at 2 and 3 years of age using semen from the same bull. In the first year, cows gestated under grazing conditions and nursed their calves in the feedlot. In the second year, the opposite occurred. Cows were weighed every 28 days during pregnancy and calves were weighed at birth and every 28 days until weaning. Ultrasound images were collected from the carcass of cows and calves. Muscle gene expression was evaluated in calves at birth and weaning. Data were analyzed by year considering the fixed effects of RFI class and FTAI protocol for variables measured in cows, and RFI class, FTAI protocol and sex for variables measured in calves. There was no effect of maternal RFI on calves performance in the first year. Lower expression of FABP4 gene and trend towards lower expression of SREBF1 and LPL genes were detected in samples collected after birth from calves born to negative RFI cows, indicating that adipogenesis was reduced during the fetal and neonatal period. In the second year, negative RFI cows had greater subcutaneous fat thickness than positive RFI cows, and their calves tended to be heavier at birth and to have less rump fat thickness at weaning. No significant differences in expression of genes studied were detected between cow RFI classes. Nellore cows classified as negative RFI consume less feed and produce calves whose growth potential is similar to that of calves produced by positive RFI cows.
Topics: Animal Feed; Animals; Cattle; Diet; Eating; Feeding Behavior; Female; Lipogenesis; Male; Muscles; Pregnancy
PubMed: 35905086
DOI: 10.1371/journal.pone.0272236