Lipid Catabolism and ROS in Cancer: A Bidirectional Liaison

Although cancer cell metabolism was mainly considered to rely on glycolysis, with the concomitant impairment of mitochondrial metabolism, it has recently been demonstrated that several tumor types are sustained by oxidative phosphorylation (OXPHOS). In this context, endogenous fatty acids (FAs) deriving from lipolysis or lipophagy are oxidised into the mitochondrion, and are used as a source of energy through OXPHOS. Because the electron transport chain is the main source of ROS, cancer cells relying on fatty acid oxidation (FAO) need to be equipped with antioxidant systems that maintain the ROS levels under the death threshold. In those conditions, ROS can act as second messengers, favouring proliferation and survival. Herein, we highlight the different responses that tumor cells adopt when lipid catabolism is augmented, taking into account the different ROS fates. Many papers have demonstrated that the pro- or anti-tumoral roles of endogenous FA usage are hugely dependent on the tumor type, and on the capacity of cancer cells to maintain redox homeostasis. In light of this, clinical studies have taken advantage of the boosting of lipid catabolism to increase the efficacy of tumor therapy, whereas, in other contexts, antioxidant compounds are useful to reduce the pro-survival effects of ROS deriving from FAO.

Developmental Programming: Prenatal Testosterone Excess on Liver and Muscle Coding and Non-Coding RNA in Female Sheep

Prenatal testosterone (T)-treated female sheep manifest peripheral insulin resistance, ectopic lipid accumulation and insulin signaling disruption in liver and muscle. This study investigated transcriptional changes and transcriptome signature of prenatal T excess-induced hepatic and muscle-specific metabolic disruptions. Genome-wide coding and non-coding (nc) RNA expression in liver and muscle from 21-month-old prenatal T-treated (T propionate 100mg intramuscular twice weekly from days 30 to 90 of gestation; Term: 147 days) and control females were compared. Prenatal T (1) induced differential expression of mRNAs in liver (15 down, 17 up) and muscle (66 down, 176 up) (FDR<0.05, absolute log2 fold change>0.5); (2) downregulated mitochondrial pathway genes in liver and muscle; (3) downregulated hepatic lipid catabolism and PPAR signaling gene pathways; (4) modulated ncRNA metabolic processes gene pathway in muscle and (5) downregulated 5 uncharacterized long ncRNA (lncRNA) in the muscle but no ncRNA changes in the liver. Correlation analysis showed downregulation of lncRNAs LOC114112974 and LOC105607806 was associated with decreased TPK1, and LOC114113790 with increased ZNF470 expression. Orthogonal Projections to Latent Structures Discriminant Analysis identified mRNAs HADHA and SLC25A45, and miRNAs MIR154A, MIR25 and MIR487B in liver and ARIH1 and ITCH and miRNAs MIR369, MIR10A and MIR10B in muscle as potential biomarkers of prenatal T-excess. These findings suggest downregulation of mitochondria, lipid catabolism, and PPAR signaling genes in liver and dysregulation of mitochondrial and ncRNA gene pathways in muscle are contributors of lipotoxic and insulin resistant hepatic and muscle phenotype. Gestational T excess programming of metabolic dysfunctions involve tissue-specific ncRNA modulated transcriptional changes.

Assessment on the oil accumulation by knockdown of triacylglycerol lipase in the oleaginous diatom Fistulifera solaris

Microalgae are promising producers of biofuel due to higher accumulation of triacylglycerol (TAG). However, further improvement of the lipid metabolism is critical for feasible application of microalgae in industrial production of biofuel. Suppression of lipid degradation pathways is a promising way to remarkably increase the lipid production in model diatoms. In this study, we established an antisense-based knockdown (KD) technique in the marine oleaginous diatom, Fistulifera solaris. This species has a capability to accumulate high content of lipids. Tgl1 KD showed positive impact on cell growth and lipid accumulation in conventional culture in f/2 medium, resulting in higher oil contents compared to wild type strain. However, these impacts of Tgl1 KD were slight when the cells were subjected to the two-stage growth system. The Tgl1 KD resulted in slight change of fatty acid composition; increasing in C14:0, C16:0 and C16:1, and decreasing in C20:5. This study indicates that, although Tgl1 played a certain role in lipid degradation in F. solaris, suppression of only a single type of TAG lipase was not significantly effective to improve the lipid production. Comprehensive understanding of the lipid catabolism in this microalga is essential to further improve the lipid production.

Copper restoration by liver Ceruloplasmin ablation ameliorates NAFLD via SCO1-AMPK-LKB1 complex

Copper is an essential nutrient and a co-factor of numerous enzymes governing a wide range of intracellular processes. Copper deficiency has emerged to be associated with various lipid metabolism diseases, including non-alcoholic fatty liver disease (NAFLD). However, the molecular mechanisms of how copper regulates lipid metabolism and is sensed remain elusive. Here, we reveal that copper elevation caused by hepatic ceruloplasmin (CP) ablation enhances lipid catabolism by promoting the assembly of copper-load SCO1/AMPK complex. We report that overnutrition-mediated CP elevation results in hepatic copper loss, and that liver-specific CP ablation counteracts this reduction in copper levels and ameliorates NAFLD in mice. Mechanistically, SCO1 constitutively interacts with LKB1 even in the absence of copper, and copper-loaded SCO1 directly tethers LKB1 to AMPK, thereby activating AMPK and consequently promoting mitochondrial biogenesis and fatty acid oxidation in hepatocytes. Therefore, this study reveals an unexpected role for AMPK to sense copper alteration via SCO1 and uncovers a previously unidentified mechanism by which copper, as a signaling molecule, improves hepatic lipid catabolism, and indicates that targeting copper-AMPK signaling pathway ameliorates NAFLD development by modulating AMPK activity.

Evidence that C/EBP-β LAP Increases Fat Metabolism and Protects Against Diet-Induced Obesity in Response to mTOR Inhibition

Aging and obesity are common risk factors for numerous chronic pathologies, and the compounding effects of old age and increased adiposity pose a serious threat to public health. Starting from the assumption that aging and obesity may have shared underpinnings, we investigated the antiobesogenic potential of a successful longevity intervention, the mTORC1 inhibitor rapamycin. We find that rapamycin prevents diet-induced obesity in mice and increases the activity of C/EBP-β LAP, a transcription factor that regulates the metabolic shift to lipid catabolism observed in response to calorie restriction. Independent activation of C/EBP-β LAP with the antiretroviral drug adefovir dipivoxil recapitulates the anti-obesogenic effects of rapamycin without reducing signaling through mTORC1 and increases markers of fat catabolism in the liver. Our findings support a model that C/EBP-β LAP acts downstream of mTORC1 signaling to regulate fat metabolism and identifies a novel drug that may be exploited to treat obesity and decrease the incidence of age-related disease.

Abstract P462: Bscl2/seipin Deficiency In Heart Causes Energy Deficit And Heart Failure Via Inducing Excessive Lipid Catabolism

Heart failure (HF) is one of the leading causes of death world-wide and is associated with cardiac metabolic perturbations. Human Type 2 Berardinelli-Seip Congenital Lipodystrophy (BSCL2) disease is caused by mutations in the BSCL2 gene. Global lipodystrophic Bscl2 –/– mice exhibit hypertrophic cardiomyopathy. Whether BSCL2 plays a direct role in regulating cardiac substrate metabolism and/or contractile function remains unknown. Here we show that mice with cardiac-specific deletion of Bscl2 ( Bscl2 cKO ) developed dilated HF. Myocardial BSCL2 deletion led to elevated ATGL expression and FA oxidation (FAO) along with reduced cardiac lipid contents. Cardiac dysfunction in Bscl2 cKO mice was independent of mitochondrial dysfunction and oxidative stress, but associated with decreased metabolic reserve and ATP levels. Importantly, heart failure in Bscl2 cKO mice could be partially reversed by pharmacological inhibition of FAO, or prevented by high fat diet (HFD) feeding. Lipidomic analysis further identified markedly reduced glycerolipids, glycerophospholipids, NEFA and acylcarnitines in Bscl2 cKO hearts, which were partially normalized by FAO inhibition or HFD. Our study reveals a new form of HF with excessive lipid catabolism, and identifies a crucial cardiomyocyte-specific role of BSCL2 in controlling cardiac lipid catabolism, energy state and contractile function. It also provides novel insights into metabolically treating energy-starved HF using FAO inhibitor or HFD.