Anaplerotic Role of Glucose in the Oxidation of Endogenous Fatty Acids during Dengue Virus Infection

Abstract

Dengue virus infection is a major cause of human arbovirosis, for which clinical and experimental evidence supports the idea that liver dysfunction and lipid metabolism disorders are characteristics of severe disease. Analyzing mitochondrial bioenergetics, here we show that infection of hepatic cells with dengue virus favors the cellular capacity of metabolizing glucose, impairing the normal metabolic flexibility that allows the oxidative machinery to switch among the main energetic substrates. However, instead of being used as an energy source, glucose performs an anaplerotic role in the oxidation of endogenous fatty acids, which become the main energetic substrate during infection. Taken together, the results shed light on metabolic mechanisms that may explain the profound alterations in lipid metabolism for severe dengue patients, contributing to the understanding of dengue physiopathology.

Cyclin-Dependent Kinases 8 and 19 Regulate Host Cell Metabolism during Dengue Virus Serotype 2 Infection

“…Expression of these four genes was not upregulated during DENV2 infection of Huh7 cells (data not shown). This is in line with previous work demonstrating an anapleurotic role for HK2 in the production of metabolic intermediates rather than an ATP-producing role [7,8].…”

“…Viral replication places increased demands for production of ATP and metabolites on the host cell [3][4][5]. To meet these demands, viruses manipulate the intracellular environment of the host cell by remodeling cellular structures and by reprogramming cellular metabolism to increase the expression of key metabolic enzymes [6][7][8][9][10][11][12][13][14].…”

“…Sequential infections with different DENV serotypes are associated with dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), which are life threatening in 15% of patients [17,18]. Of the four serotypes, DENV2 has been shown to rely on increased glucose uptake and enhanced glucose metabolism to provide necessary metabolic intermediates for viral replication [7,8,19]. DENV2 infection also induces autophagy and lipophagy for efficient replication [11,[20][21][22][23][24].…”

Glutaminolysis and Glycolysis Are Essential for Optimal Replication of Marek’s Disease Virus

“…MDV is a highly cell-associated alphaherpesvirus which infects chickens and causes a deadly lymphoma (5,21,22) and induces immunosuppression (23,24). MDV infection disturbs lipid metabolism and causes atherosclerosis, which can be inhibited by vaccine-induced immunity (9,13,25). Chicken feather follicles are the only cells capable of producing cell-free virus; otherwise, the virus is completely cell associated (21).…”

“…However, it is still unknown whether MDV-infected cells can utilize metabolites derived from fatty acid ␤-oxidation, an important mitochondrion and peroxisome aerobic process, for generation of energy. This process has been shown to be important in replication of Dengue virus (DENV) (13,14).…”