Paper of the Month- Archive

August 8, 2016- Contributed by Leah Burkovsky

 

Rebalka et al. Statin Therapy Alters Lipid Storage in Diabetic Skeletal Muscle. Frontiers in Endocrinology. 2016 July 19; 7: 95.

Statins are a group of drugs that reduce cholesterol levels and as a result, reduce the risk of cardiovascular disease. However, a clinical side effect of statins is the development of myopathy. Diabetic individuals already suffer from muscular maladies. This paper looks at the effects of fluvastatin treatment on muscles in wild type (WT) and streptozotocin (STZ)-induced diabetic mice over the course of 24 days. Muscle morphology, lipid levels and lipid transporter content were examined. They found that myopathy was not exacerbated in diabetic mice treated with fluvastatin. They did note that only fluvastatin-treated diabetic mice had down-regulated protein expression of lipid transporters FAT/CD36 and FABPpm in skeletal muscles. However, there was no difference in mRNA content.  Fluvastatin also significantly increased ectopic lipid deposition within the muscles of diabetic mice. Since there is an association between ectopic lipid deposition in skeletal muscles and the development of insulin resistance, the authors suggest that further investigation in needed into the impact of statins in humans with diabetes. 

August 1, 2016

 

Revelo et al. Nucleic acid-targeting pathways promote inflammation in obesity induced insulin resistance. Cell Reports. 2016 July 16(3): 717-30.

This papers points to the release of nucleic acids (and associated antigens) and their subsequent activation of pattern-recognition receptors (TLR 7/9) in the propogation of insulin resistance that develops during obesity. Adipose tissue macrophages and a population of dendritic cells in the liver facilitate this response, which worsens metabolic outcomes. Targeting TLRs had a positive effect, whereby insulin resistance and inflammation was attenuated. This points to potential therapies that target nucleic acid-sensing systems in obestiy. 

July 25, 2016- contributed by Rebecca Yaworski

 

Nishiyama et al. Identification and functional analysis of choline transporter in tongue cancer: A novel molecular target for tongue cancer therapy. J Pharm Sci. 2016 June 133; 2: 101-109.

For all cells the uptake of choline is essential, both as a precursor in the synthesis of the major membrane phospholipid, phosphatidylcholine (PC), and in the synthesis of the methyl donor betaine. However the importance of choline uptake is exemplified in the face of cancer as multiplying cells require an extensive and continuous supply of membrane lipids. Based on this premise Nishiyama et al., demonstrate the role of CTL1 in the uptake of choline within HSC-3 tongue carcinoma cells and further demonstrate the inverse relationship between choline uptake and cancer cell survival. The loss of CTL1 function through siRNA knockdown as well as through drug inhibition was shown to result in the induction of cancer cell apoptosis. In addition, caspases-3/7 activity was also observed to increase following choline deficiency however the mechanism underlying this effect was not investigated nor was its connection to the induction of apoptosis. In conclusion the functional inhibition of CTL1 is suggested as a potential target for future cancer therapy research.  

July 18, 2016- contributed by Shayne Snider

 

Perry et al. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome.

Nature. 2016 June 8; 534: 213-17.

A new and promising area of research is examining the role the gut microbiome plays in medicine and its role in the development of disease. In this Nature paper, Perry et al. investigate the role of the gut microbiome in the regulation of acetate levels and the development of obesity. In examining mice fed high fat and normal chow diets, they discovered that high fat diets increased acetate tissue content and drove increased levels of insulin production. This increase was dependent on the activation of the parasympathetic nervous system. Then, germ-free mice and germ-free mice given a faecal transplant were fed with either a high fat or chow diet and acetate incorporation, parasympathetic activation, and triacylglycerol levels were observed. Mice fed a high fate diet showed increased tissue acetate levels, higher plasma gastrin and ghrelin concentrations, and higher liver and skeletal muscle triacylglycerol levels. These findings indicate that the gut microbiota play a significant role in the development of metabolic disease.  

July 11, 2016- contributed by Kaitlyn Margison

 

Funai et al. Skeletal muscle phospholipid metabolism regulates insulin sensitivity and contractile function. Diabetes. 2016 Feb; 65(2): 358-370.

Although the connection between obesity and insulin resistance is widely studied and communicated, there is a lack of understanding for the mechanism by which excess lipids interact with muscle to affect glucose metabolism. This group uses a series of high fat diet fed mice to highlight the role of skeletal muscle Choline/ethanoalamine phosphotransferase 1 (CEPT1) in the regulation of glucose metabolism. CEPT1 is the terminal enzyme in the Kennedy pathway of phospholipid synthesis, responsible for the synthesis of PE and PC. An alteration in PE affects sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). Decreased SERCA activity has been linked to increased insulin sensitivity as well as muscle weakness. As a result, high fat diet fed mice with skeletal muscle- specific CEPT1 deficiency showed an increase in insulin sensitivity and exercise intolerance. This work demonstrates the mechanism by which increased expression of CEPT1 in obese individuals in responsible for insulin resistance. Moreover, it highlights the need for novel therapies which allow for sustaining muscle contraction in obese individuals.  

July 4, 2016- contributed by Nick LeBlond

 

Pastore et al. TFEB and TFE3 Cooperate in the Regulation of the Innate Immune Response in Activated Macrophages. Autophagy. 2016 May 12; Epub ahead of print.

The lysosome is an important organelle participating in many critical roles within metabolism and host defense. Transcription factor EB (TFEB) is the master regulator of lysosomal biogenesis and autophagy (a lysosome-dependent recycling pathway), however recently it has been evidenced that transcription factor 3 (TFE3) regulates similar subsets of genes as TFEB. Pastore et al. have shown that TFEB and TFE3 co-operate to stimulate the expression of genes responsible for lysosomal biogenesis and autophagy and show some functional redundancy. Interestingly, this group reported a novel role for TFEB and TFE3 in macrophage activation and immune response. They have revealed that both TFEB and TFE3 are required from normal transcription of a number of cytokines, chemokines, and other immunological genes in response to the bacterial endotoxin lipopolysaccharide.  

June 27, 2016- contributed by Leah Burkovsky

 

Sun et al. mi-R21 regulated triglyceride and cholesterol metabolism in non-alcoholic fatty liver disease by targeting HMGCR. International Journal of Molecular Medicine 2015 Jan 16; 35: 847-853.

Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive accumulation of fat in the liver. It has been suggested that microRNA-21 (miR-21) is associated with NAFLD. In this study, Sun et. al investigated the effects of miR-21 on triglyceride and cholesterol metabolism using cellular models. The serum levels of miR-21 were lower in patients with NAFLD compared with healthy controls. It was determined that 3-hydroxy-3-methylflutaryl-co-enzyme A reductase (HMGCR) was a direct target of miR-21 using a luciferase reporter assay. miR-21 affects both HMGCR transcript degradation and protein translation, and decreases levels of triglycerides, free cholesterol and total cholesterol. miR-21 may be a useful biomarker for the diagnosis and treatment of NAFLD.  

June 20, 2016-

 

Sallam et al. Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis. Nature. 2016 June 2; 534, 124-128. 

The regulation of cholesterol homeostasis is multifaceted and complex. The liver x receptors (LXRs), are a family of transcriptional regulators that can govern cholesterol and fatty acid metabolism in the liver. In this recent Nature Letter, the Tontonoz group identify a long non-coding RNA, termed LeXis, which governs hepatic cholesterol metabolism, in part via actions that affect binding of a ribonucleoprotein to cholesterol biosynthetic genes. This study furthers our understanding of regulatory RNAs and their important roles in regulating lipid metabolism. 

June 13, 2016- Contributed by Rebecca Yaworski

 

Manoj Amrutkar et al. Protein kinase STK25 controls lipid partitioning in hepatocytes and correlates with liver fat content in humans Diabetologia. 2016 Feb 16; 59, 341-353. 

 

In continuation of their 2015 article focusing on the role of serine/threonine protein kinase 25 (STK25) in the progression of liver steatosis, in this article Amrutkar et al. provide a new mechanistic understanding of STK25’s role in hepatic lipid partitioning. Following the overexpression of STK25 in hepatocyte cell lines, an increase in lipid deposition was observed, this accumulation was found to be a result of STK25’s suppression of b-oxidation and VLDL-TAG secretion while simultaneously promoting LD anabolism through enhanced TAG synthesis. Conversely, knockdown of STK25 resulted in increase b-oxidation, VLDL-TAG secretion and decreased TAG synthesis in both cell line and in-vivo experiments. Disruption of STK25 function was also found to protect against diet-induced liver steatosis in mouse models and improve insulin and AICAR sensitivity in hepatocyte cell lines. This article provides insight into the cell-specific role of STK25 in maintaining liver lipid homeostasis, future studies in this area are aimed at evaluating the potential of STK25 as a therapeutic target for the prevention and/or treatment of lipid related liver disease.

June 6, 2016- Contributed by Shayne Snider

 

van Stijn et al. Macrophage polarization phenotype regulates adiponectin receptor expression and adiponectin anti-inflammatory response. FASEB J. 2015 Feb 29; 2: 636-49. 

 

Adiponectin is an adipokine that is critical in the regulation of immunometablism and in the development of metabolic disease. In this study, van Stijn et al. examined the relationship between adiponectin treatment and macrophage polarization. M1 polarization decreased the expression of the adiponectin receptor, while M2 stimulation exhibited no effect. Polarized macrophages treated with adiponectin also exhibited altered inflammatory states, with M1 macrophages increasing pro-inflammatory cytokine production and adiponectin receptor expression. M2 macrophages treated with adiponectin showed an increase in IL-10 production, although no change in adiponectin receptor expression was observed. This study suggests a link exists between adiponectin signaling and macrophage polarization exists, which could modulate immunometabolic disorders.

May 30, 2016- Contributed by Kaitlyn Margison

 

Wu, Y et al. Activation of AMPKa2 in adipocytes is essential for the nicotine induced insulin resistance in vivo. Nature Medicine. 2015 March 23; 21: 373-382. 

 

For more than 60 years, cigarettes have been linked to weight loss. Simultaneously however, cigarette smoking has also been linked to insulin resistance and hyperinsulinemia.  As these two effects are more commonly observed inversely to one another, the mechanism responsible for this effect is poorly understood. This report demonstrates how nicotine selectively activates AMPKa2,  triggering a phosphorylation cascade, causing an increase in lipolysis and hence a reduction in body weight. Consequently, an increase in lipolysis leads to an increase in circulating free fatty acids, leading to insulin resistance in insulin-sensitive tissues. After thorough experimentation and understanding of this mechanism, this group was able to show the potential of anti-lipolytic drugs as treatment for insulin resistance in smokers and individuals undergoing nicotine-based smoking cessation therapy. This report highlights the importance of the mechanistic investigation of AMPK activators and their effects for therapeutic potential and treatment.

May 23, 2016- Contributed by Nick LeBlond

 

Martinez et al. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Nature. 2016 April 20; 533: 115-119. 

 

Autophagy, a lysosomal-dependent ‘self-eating’ pathway, is an evolutionarily conserved pathway implicated in cellular metabolism, organelle turnover, and pathogen defense. Albeit a complex process composed of numerous proteins and complexes, ‘normal’ or canonical autophagy is initiated by the kinase ULK1. Martinez et al. have recently explored a non-canonical autophagy pathway that bypasses ULK1 and its initiation complex. This group evidenced through genetic disruption in non-canonical (but not normal) autophagy lead to increased body weight, production of auto-antibodies, and increased pro-inflammatory cytokines, which are symptoms to observe in systemic lupus erythematosus (SLE). This research sheds light on alternative pathways under the umbrella of autophagy that may be able to be therapeutically exploited for the treatment of SLE.

May 16, 2016- Contributed by Leah Burkovsky

 

Xu X et al. Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metabolism. 2013 Dec 3; 18(6): 816-830. 

 

Obesity activates a complex systemic immune response. Studies often focus on the classic inflammatory responses. However, this paper looks at the non-inflammatory functions of adipose tissue macrophages (ATMs). In adipose tissue, obesity (or an increase in adiposity) upregulates the expression of genes involved in lipid uptake and storage, and upregulates the expression of lysosomal genes. This was demonstrated by transcriptional profiling of lean and obese mice. As a result, obesity increases lysosomal metabolism of lipids by ATMs.  Since the development of metabolic diseases is related to the storage of lipids by adipose tissues, the role of ATM lysosome function may provide insights and potential therapeutic targets for treating obesity-related diseases.

May 9, 2016- Contributed by Rebecca Yaworski

 

Fang and Lazar. Dissecting the Rev-erba cistrome and mechanisms controlling

circadian transcription in liver Cold Spring Harbor Laboratory Press

 

Rev-erbα is a nuclear receptor which maintains the circadian rhythm in peripheral metabolic tissues. Through the recruitment of NCoR and HDAC3, Rev-erbα inhibits the transcription of RORE and RevDR2 associated genes during periods of fasting or low nutrient intake such as during the day for nocturnal animals like the mouse. In the 2015 article by Fang and Lazar, the role of Rev-erbα in maintaining a circadian rhythm through the regulation of metabolic gene transcription was examined in the liver of mice. With the use of a knock-out model, it was discovered that Rev-erbα inhibits the transcription of genes associated with night time lipid metabolism by suppressing the activity of E4BP4-mediated gene transcription during the day. The knock-out of Rev-erbα resulted in the inappropriate transcription of night-time lipid metabolizing genes during the day, as well as decreased expression of day-time liver genes due the inhibitory activity of E4BP4, typically suppressed by Rev-erbα. This article furthers our understanding of the mechanisms underlying peripheral circadian rhythmicity while encouraging further exploration into its regulation and influence on hepatic lipid metabolism.

May 2, 2016-

 

Jang et al. A branched-chain amino acid metabolite drives vascular fatty acid transport

and causes insulin resistance Nature Medicine, April; 22(4), 461-6. 

 

Branch chain amino acid metabolism is known to be implicated in metabolic dysfunction, but the mechanisms by which this might regulate insulin sensitivity has remained unclear. Recent work has determined that a metabolite intermediate in the processing of valine, 3-isohydroxybutyrate (3-HIB), acts as a paracrine factor to increase the uptake of fatty acids by skeletal muscle. This results in the accumulation of lipids into the muscle and subsequently insulin resistance. Importantly, obese mice and type 2 diabetic human skeletal muscle showed an increase in 3-HIB levels. This points to the importance and therapeutic potential of targeting this type of pathway to combat insulin resistance.

April 25, 2016- Contributed by Shayne Snider

 

Kwak et al. Bortezomib attenuates palmitic acid-induced ER stress, inflammation and insulin resistance in myotubes via AMPK dependent mechanism Cell Signal, epub ahead of print 

 

Bortezomib, an anti-cancer drug, has been shown to induce ER stress by inhibiting proteasomal degradation. In this study, Kwak et al. investigated whether Bortezomib treatment could influence palmitic acid-induced ER stress, which contributes to type 2 diabetes and insulin resistance. Upon treatment with low levels, Bortezomib attenuated palmitic acid-induced ER stress. Glucose uptake and AKT phosphorylation were also reduced in response to Bortezomib treatment. These protective effects were determined to be AMPK dependent. Administration of Bortezomib to obese mice also showed an improvement in the pathogenesis of metabolic disease, increasing AMPK phosphorylation and insulin sensitivity while decreasing ER stress and JNK phosphorylation. These findings point to Bortezomib as a novel drug for targeting metabolic disease.

April 18, 2016- Contributed by Nick LeBlond

 

Fond et al. Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1.

J Clin Invest, June; 125(7), 2748–2758 

 

ABCA1 is a key lipid transport protein that plays an important role in macrophages, facilitating cholesterol export to nascent HDL. Fond et al. have recently uncovered a novel plasma-membrane mediated signaling pathway that stimulates ABCA1 expression independently of the LXR. Using various genetic knockout models the Ravichandran group identified that the phosphatidylserine present on apoptotic cells was able to signal through the phagocytic receptor BAI1 to upregulate ABCA1 expression. Genetically knocking out BAI1 in the dyslipidemic LDLR mouse line resulted in increased macrophage burden and apoptotic cells in atherosclerotic plaque.

April 11, 2016

Yang W et al. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism

Nature 2016 epub ahead of print

 

Immunotherapy uses the cytotoxic capacity of immune cells to combat tumour growth. CD8+ T cells are amoung those cells being investigated for their immunotherapeutic potential. Yang et al. have recently shown that when cholesterol metabolism is altered, more specifically when the esterification of free cholesterol with a fatty acid by the enzyme ACAT is inhibited, CD8+ T cells are more cytotoxic. The genetic and chemical inhibition of ACAT activity causes increased membrane cholesterol and alters membrane properties to enhance CD8+ (but not CD4+) T cell proliferation and effector functions. This ultimately lessened tumor progression and metastasis.

April 4, 2016

            Keestra-Gounder MA et al. NOD1 and NOD2 signaling links ER stress with inflammation.

Nature 2016 epub ahead of print

 

NOD1 and NOD2 are intracellular pattern recognition receptors that play a major role in sensing tissue damage and pathogen invasion. Work from the Schertzer group at McMaster has unveiled potential divergent roles of NOD1 and NOD2 in various metabolic processes. Here, the authors link the ER stress in response to known ER stress agents as well as bacterial infection with NOD1/2 dependent signaling. This aligns a pro-inflammatory response for both NOD1 and NOD2 in the face of ER-stress-induced inflammation.

March 28, 2016- Contributed by Shayne Snider

 

            York AG et al. Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling.

Cell 2015 Dec; 163(7): 1716-29

 

Lipid metabolism and inflammatory signaling have been intimately connected in the context of both microbial infections and metabolic disease. In their recent Cell paper, the Bensinger group of UCLA showed by isotope labeling that TLR activation by type 1 interferon (IFN) alters the metabolic state of macrophages, increasing the import of cholesterol and long chain fatty acids while decreasing synthesis. They also showed that the type 1 IFN response is promoted by limiting flux through the cholesterol biosynthetic pathway and that replenishing low cholesterol levels can reduce the IFN response.

March 21, 2016

Huang SC et al. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nature Immunology 2014 Sep;15(9):846-55.

 

Although macrophages exist along a continum of "polarization" states, they are typically thought of as alternative or classically activated (anti- vs. pro-inflammatory). In a recent paper from the Pearce group, they demonstrate that alternative activation via the IL-4R requires fatty acids made available via lipophagy and the lysosomal degradation of lipids. The capacity to process and oxidize fatty acids was shown to be essential for the anti-inflammatory polarization state.

March 11, 2016

Toyama EQ et al. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress.

Science 2016 Jan 15;351(6270): 275-81.

 

AMPK is known to have many roles in mitochondrial homeostasis, including biogenesis and mitophagy. New work from the Shaw lab has identified mitochondrial fission factor (MFF) as an AMPK substrate and has demonstrated its necessity for mediating the effects of AMPK activation.

May 22, 2015

Selathurai et al. The CDP-Ethanolamine pathway regulates skeletal muscle DAG content and mitochondrial biogenesis without altering insulin sensitivity

Cell Metabolism. 2015 May 5;21(5): 718-30.

 

The CDP ethanolamine pathway is critical for PE synthesis and life. Dr. Fullerton's PhD involved characterizing a global knockout of the Pcyt2 gene (critical for PE). In this paper from Clinton Bruce's lab, Pcyt2 was deleted specifically in skeletal muscle. With PE synthesis decreased, there is a reciprical increase in diacylglycerol, however this was not associated with deleterious effects on metabolic parameters such as obesity or insulin resistance. Interestingly, skeletal muscle deletion of Pcyt2 increased mitochondrial biogenesis. 

April 22, 2015

Kim et al. Hepatic TRAP80 selectively regulates the activity of liver x receptor

Journal of Clinical Investigation. 2015; 125(1): 183-93.

 

The liver x receptor (LXR) is a transcriptional activator and regulates many important aspects of lipid metabolism. In macrophages, its activation stimulates cholesterol efflux and diminishes cholesterol uptake (both protective mechanisms). The problem has been that treatment with LXR agonists as a therapy for metabolic disease results in hepatic lipid accumulation- since in the liver, LXR targets SREBP1-C to induce lipogenesis. This study identifies TRAP80 as the link between LXR and SREBP1-C, demonstrating that if you inhibit/block/knockdown TRAP80, it is possible to uncouple and exploit the beneficial effects of LXR activation on liver lipid metabolism. This could open the door for combinational types of therapies for fatty liver disease.  

April 16, 2015

Duca et al. Metformin activates a duodenal Ampk–dependent

pathway to lower hepatic glucose production in rats

Nature Medicine. 2015 Apr 6. doi: 10.1038/nm.3821. [Epub ahead of print]

 

In back to back publications, Tony Lam's lab has uncovered that the most common anti-diabetic drug metformin activates AMPK in the duodenum, which signals to lower hepatic glucose production in rats. Intraduodenal infusion of metformin required AMPK to lower hepatic glucose, through mechanisms that likely invovle GLP-1r and PKA. This is yet another study to highlight new aspects of metformin's mode of action in a diabetic context.

April 9, 2015

Sekimoto et al. Visualized macrophage dynamics and significance of S100A8 in obese fat

Proc Natl Acad Sci U S A. 2015 Apr 6. pii: 201409480. [Epub ahead of print]

 

This paper is the first to show the migration and movement of macrophages within adipose tissue during obesity using live intravital multiphoton imaging of a fluorscent transgene (amazing movies to show movement of live cells in adipose).