Complex lipid metabolic remodeling is required for efficient hepatitis C virus replication

The hepatitis C virus (HCV) life cycle is tightly linked to the host cell lipid metabolism with the endoplasmic reticulum–derived membranous web harboring viral RNA replication complexes and lipid droplets as virion assembly sites. To investigate HCV-induced changes in the lipid composition, we performed quantitative shotgun lipidomic studies of whole cell extracts and subcellular compartments. Our results indicate that HCV infection reduces the ratio of neutral to membrane lipids. While the amount of neutral lipids and lipid droplet morphology were unchanged, membrane lipids, especially cholesterol and phospholipids, accumulated in the microsomal fraction in HCV-infected cells. In addition, HCV-infected cells had a higher relative abundance of phosphatidylcholines and triglycerides with longer fatty acyl chains and a strikingly increased utilization of C18 fatty acids, most prominently oleic acid (FA [18:1]). Accordingly, depletion of fatty acid elongases and desaturases impaired HCV replication. Moreover, the analysis of free fatty acids revealed increased levels of polyunsaturated fatty acids (PUFAs) caused by HCV infection. Interestingly, inhibition of the PUFA synthesis pathway via knockdown of the rate-limiting Δ6-desaturase enzyme or by treatment with a high dose of a small-molecule inhibitor impaired viral progeny production, indicating that elevated PUFAs are needed for virion morphogenesis. In contrast, pretreatment with low inhibitor concentrations promoted HCV translation and/or early RNA replication. Taken together our results demonstrate the complex remodeling of the host cell lipid metabolism induced by HCV to enhance both virus replication and progeny production.     

Wide-gene expression analysis of lipid-relevant genes in nutritionally challenged gilthead sea bream (Sparus aurata)

Disturbances of lipid metabolism are a major problem in livestock fish and the present study analysed the different tissue expression patterns and regulations of 40 lipid-relevant genes in gilthead sea bream. Nineteen sequences, including fatty acid elongases (4), phospholipases (7), acylglycerol lipases (8) and lipase-maturating enzymes (1), were new for gilthead sea bream (GenBank, JX975700, JX975701, JX975702, JX975703, JX975704, JX975705, JX975706, JX975707, JX975708, JX975709, JX975710, JX975711, JX975712, JX975713, JX975714, JX975715, JX975716, JX975717 and JX975718). Up to six different lipase-related enzymes were highly expressed in adipose tissue and liver, which also showed a high expression level of Δ6 and Δ9 desaturases. In the brain, the greatest gene expression level was achieved by the very long chain fatty acid elongation 1, along with relatively high levels of Δ9 desaturases and the phospholipase retinoic acid receptor responder. These two enzymes were also expressed at a high level in white skeletal muscle, which also shared a high expression of lipid oxidative enzymes. An overall down-regulation trend was observed in liver and adipose tissue in response to fasting following the depletion of lipid stores. The white skeletal muscle of fasted fish showed a strong down-regulation of Δ9 desaturases in conjunction with a consistent up-regulation of the “lipolytic machinery” including key enzymes of tissue fatty acid uptake and mitochondrial fatty acid transport and oxidation. In contrast, the gene expression profile of the brain remained almost unaltered in fasted fish, which highlights the different tissue plasticity of lipid-related genes. Taken together, these findings provide new fish genomic resources and contribute to define the most informative set of lipid-relevant genes for a given tissue and physiological condition in gilthead sea bream.     

STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses

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