Cutting off Lipid Supply Halts HCV

Image: Flickr - bibendum84
New research has shown that compounds that affect cellular energy status could also be used to treat hepatitis C virus (HCV) infections. Metformin, which is used to treat type II diabetes, and 5-amino-1-β-D-ribofuranosyl-1H-imidazole-4-carboxamide (AICAR), which has been shown to mimic the beneficial effects of exercise in mice, stimulate AMP-activated protein kinase (AMPK). AMPK is a key sensor of cellular energy status and regulates both lipid and glucose metabolism to maintain cellular energy balance and protect against metabolic stress. An increase in the AMP/ATP ratio initiates an AMPK-mediated switch from activities that consume ATP, such as lipid production, to activities that produce ATP, such as lipid and glucose oxidation.

Infection with viruses might be expected to activate AMPK because of the energy demands put on the cell by viral replication, but research led by scientists at the University of Leeds has shown instead that HCV switches off AMPK so that the cell continues to produce the lipids needed to provide new viral particles with a protective outer coat. When the team treated HCV-infected cells with metformin or AICAR, AMPK activity was restored and viral replication was inhibited.

The team plan to carry out a small scale clinical trial to investigate the effects of AMPK activators in HCV infection and hope that such drugs may provide much-needed new treatments for HCV.

The study is published in the Proceedings of the National Academy of Science.

Cholesterol – All in the Mind?

Image: Adapted from Flickr - Horia Varlan
Cholesterol is essential for all animal life but high levels of cholesterol – when associated with low density lipoprotein (LDL) – are linked to an increased risk of atherosclerosis, heart disease and stroke. Circulating cholesterol can also be transported by high density lipoprotein (HDL); HDL is believed to be able to remove cholesterol from atheroma within arteries and cholesterol associated with HDL is considered to be beneficial for cardiovascular health. Cholesterol levels are determined by dietary intake, de novo synthesis and secretion by the liver: cholesterol absorption blockers and HMG-CoA reductase inhibitors (statins), which block cholesterol synthesis, are used clinically to reduce cholesterol levels.

A study led by researchers at the University of Cincinnati has now identified a new potential target for the control of cholesterol. The study, carried out in mice, found that circulation of cholesterol is regulated in the brain by the ‘hunger hormone’, ghrelin, which inhibits the melanocortin 4 receptor (MC4R) in the hypothalamus and is important for the regulation of food intake and energy expenditure. Increased levels of ghrelin were associated with increased levels of circulating HDL cholesterol, which the authors attribute to a reduction in the uptake of cholesterol by the liver. Genetically deleting or chemically blocking MCR4 in the CNS also led to increased levels of HDL cholesterol, suggesting that MCR4 is key to central control of cholesterol.

More studies are need to determine whether the effects observed in mice can be applied to humans but the finding that a neural circuit may be directly involved in the control of cholesterol metabolism by the liver could provide a target for new treatments to control cholesterol.

The study is published in the journal Nature Neuroscience.

Controlling Fat Distribution

Image: Patrick Hoesly
Extreme accumulation of fat in muscle tissue is associated with cardiovascular disease and is a contributory factor in insulin resistance and type II diabetes. It is therefore important to understand the mechanisms by which fat is taken up from the bloodstream and metabolised by tissues. Surprisingly, the role of blood vessels themselves in the transport of lipids has not been clearly established. Researchers at the Karolinska Institutet have now identified a role for vascular endothelial growth factor-B (VEGF-B) in endothelial targeting of lipids to peripheral tissues.

The VEGFs and their receptors are major regulators of angiogenesis and pharmacological intervention, for example with bevacizumab (a monoclonal antibody specific for VEGF-A), has been successfully exploited in oncology. This latest study has shown that VEGF-B, in mice, controls endothelial uptake of fatty acids via transcriptional regulation of vascular fatty acid transport proteins. Mice that were deficient in VEGF-B (Vegfb-/-) showed reduced uptake and accumulation of lipids in muscle, heart and brown adipose tissue. Instead, the Vegfb-/- mice preferentially transported lipids to white adipose tissue, resulting in a small weight increase. This regulation was mediated by VEGF receptor 1 and neuropilin 1 expressed by the endothelium.

The authors of the study, published in Nature, propose that this new role for VEGF-B could potentially lead to novel strategies to modulate pathological lipid accumulation in diabetes, obesity and cardiovascular diseases.

Blocking Lipid Droplet Hydrolysis May Be Beneficial

oil drops
Image: Flickr - Fox Kiyo
Fatty acids can be stored as triacylglycerol in lipid droplets, typically within adipose tissue, and then later released by the action of triacylglycerol hydrolase (TGH, also known as carboxylesterase-3, Ces3). Under normal circumstances, the released fatty acids provide an energy source, but excessive accumulation of triacylglycerol in peripheral tissues is associated with obesity and is a risk factor for type II diabetes and cardiovascular disease.

Researchers at the University of Alberta, Canada, reasoned that blocking the action of TGH would lead to better blood lipid profiles, but might also result in accumulation of triacylglycerol in the liver. However, they have found that mice lacking TGH (tgh-/-) display global metabolic benefits with no obvious down-side. In both fasted- and fed-states, the animals had reduced plasma triacylglycerol, apolipoprotein B, and fatty acid levels. Despite the attenuation of very low-density lipoprotein (VLDL) secretion, TGH deficiency did not increase hepatic triacylglycerol levels. The tgh-/- mice exhibited increased food intake and energy expenditure without change in body weight, and these metabolic changes are accompanied by improved insulin sensitivity and glucose tolerance.

The authors of the study, published in Cell Metabolism, suggest that pharmacological inhibition of TGH could be a useful therapeutic target, although cautioning that further work is required. It may be desirable to target TGH in specific tissues (e.g. hepatic versus adipose) but those subtleties have yet to be established.

MAGL Contributes to Aggressiveness in Cancer

white tiger
Image: Flickr - Tambako the Jaguar
Despite a growing understanding that the conversion of normal cells into cancerous cells is accompanied by metabolic changes, it remains unclear whether many of these changes play crucial roles in malignancy and disease progression. Increased lipid synthesis by fatty acid synthase has been suggested to contribute to cancer growth through both metabolic and signalling pathways. Researchers at the Scripps Institute reasoned that increased lipid synthesis must be accompanied by a lipolytic pathway to liberate stored fatty acids and have now shown that levels of monoacylglycerol lipase (MAGL) are highly elevated in aggressive cancer cells compared with less aggressive cancer cells and that this lipase, through hydrolysis of monoacylglycerols (MAGs), controls free fatty acid (FFA) levels in cancer cells.

JZL184 structure
The resulting MAGL-FFA pathway promotes migration, survival, and in vivo tumour growth. Aggressive cancer cells thus partner lipogenesis with high lipolytic activity to generate an array of pro-tumorigenic signals that support their malignant behaviour. Treatment with the selective MAGL inhibitor, JZL184, significantly reduced FFA levels in aggressive cancer cells, a finding that contrasts with the function of MAGL in normal tissues, where the enzyme does not generally control FFA levels. Knock down of MAGL activity using shRNA probes in aggressive melanoma, ovarian and breast cancer cells reduced MAGL activity by 70%–80%, with corresponding elevations in MAGs and reductions in FFAs. shMAGL cancer cell lines showed reduced in vitro migration, invasion and survival under serum starvation conditions. Treatment with JZL184 also reduced cancer cell migration, but not survival, perhaps indicating that maximal effects on aggressiveness need sustained inhibition of MAGL. shMAGL cancer cells also showed markedly reduced tumour growth rates in subcutaneous xenograft transplantation studies performed in immune-deficient mice.

Daily treatment of mice bearing MAGL-expressing tumours with JZL184 (40 mg/kg po) produced similar impairments in tumour growth rates. Addition of palmitic or stearic acid, two principal FFAs regulated by MAGL in aggressive cancer cells, to cells with genetically or pharmacologically reduced levels of MAGL restored their migratory activity in vitro. Similarly, tumour growth was enhanced in MAGL-deficient xenografts when the mice were fed a high fat diet. Cancer cells engineered to stably over-express MAGL also showed significantly reduced MAGs and elevated FFAs, a profile that was accompanied by increased migration, invasion and survival in vitro and enhanced tumour growth in vivo.

The effects of MAGL on cancer aggressiveness were found not to be mediated by endocannabinoid signalling but are suggested instead to be, at least in part, caused by increased production of bioactive lipids such as LPA and PGE2 that act on GPCRs to promote high migratory activity.

Both in vitro and in vivo studies showed that aggressive cancer cells acquire the ability to liberate FFAs by increased expression of MAGL and that this contributes to the aggressive phenotype. Since MAGL is not required for cell survival, but instead promotes progression to a more aggressive phenotype, if shown to slow tumour progression in people, inhibitors of MAGL may have a better safety profile and offer advantages over existing treatments for cancer.

The study is published in the journal Cell.

New Role for Multi-Tasking Lipid

multitaskingSince the mid-1990s, sphingosine-1-phosphate (S1P) has become one of the most widely studied lipid mediators. Many of the biological effects of S1P are mediated by signalling through cell surface receptors but researchers led by a team at Virginia Commonwealth University School of Medicine have now discovered a new role for this versatile lipid. Writing in the September 4th issue of the journal Science, they report that S1P is also produced in the cell nucleus by type 2 sphingosine kinase and plays an important role in gene regulation by inhibiting histone deacetylases (HDACs). Histones are the main protein component of chromatin and play a role in gene regulation, a function which is further refined by post-translational modifications. Acetylation of positively charged amino groups on the histone by histone acetyltransferase enzymes reduces its ability to bind to negatively charged phosphate residues on DNA and allows gene transcription to take place. HDACs are a family of enzymes that remove these acetyl groups, increasing binding to DNA and preventing transcription. The use of synthetic HDAC inhibitors as chemotherapeutic agents to treat a variety of cancers is being explored but physiological regulators of HDACs had not previously been identified. The new study shows that S1P is an important endogenous epigenetic regulator of gene expression and may help in the design of new HDAC inhibitors.