Inhibition of Granuloma Triglyceride Synthesis Imparts Control of Mycobacterium tuberculosis Through Curtailed Inflammatory Responses

Lipid metabolism plays a complex and dynamic role in host-pathogen interaction during Mycobacterium tuberculosis infection. While bacterial lipid metabolism is key to the success of the pathogen, the host also offers a lipid rich environment in the form of necrotic caseous granulomas, making this association beneficial for the pathogen. Accumulation of the neutral lipid triglyceride, as lipid droplets within the cellular cuff of necrotic granulomas, is a peculiar feature of pulmonary tuberculosis. The role of triglyceride synthesis in the TB granuloma and its impact on the disease outcome has not been studied in detail. Here, we identified diacylglycerol O-acyltransferase 1 (DGAT1) to be essential for accumulation of triglyceride in necrotic TB granulomas using the C3HeB/FeJ murine model of infection. Treatment of infected mice with a pharmacological inhibitor of DGAT1 (T863) led to reduction in granuloma triglyceride levels and bacterial burden. A decrease in bacterial burden was associated with reduced neutrophil infiltration and degranulation, and a reduction in several pro-inflammatory cytokines including IL1β, TNFα, IL6, and IFNβ. Triglyceride lowering impacted eicosanoid production through both metabolic re-routing and via transcriptional control. Our data suggests that manipulation of lipid droplet homeostasis may offer a means for host directed therapy in Tuberculosis.

Inhibition of granuloma triglyceride synthesis imparts control of Mycobacterium tuberculosis through curtailed inflammatory responses

Lipid metabolism plays a complex and dynamic role in host-pathogen interaction during Mycobacterium tuberculosis infection. While bacterial lipid metabolism is key to the success of the pathogen, the host also offers a lipid rich environment in the form of necrotic caseous granulomas, making this association beneficial for the pathogen. Accumulation of the neutral lipid triglyceride, as lipid droplets at the cellular cuff of necrotic granulomas, is a peculiar feature of pulmonary tuberculosis. The role of triglyceride synthesis in the TB granuloma and its impact on the disease outcome has not been studied in detail. Here, we identified diacylglycerol O-acyltransferase 1 (DGAT1) to be essential for accumulation of triglyceride in necrotic TB granulomas using the C3HeB/FeJ murine model of infection. Treatment of infected mice with a pharmacological inhibitor of DGAT1 (T863) led to reduction in granuloma triglyceride levels and bacterial burden. A decrease in bacterial burden was associated with reduced neutrophil infiltration and degranulation, and a reduction in several pro-inflammatory cytokines including IL1β, TNFα, IL6, and IFNβ. Triglyceride lowering impacted eicosanoid production through both metabolic re-routing and via transcriptional control. Our data suggests that manipulation of lipid droplet homeostasis may offer a means for host directed therapy in Tuberculosis.

Effect of Tomate Juice On Trigliserida Levels Of Male White Rats Induced by Alloxan

Background: Tomato juice is believed to affect triglyceride levels in the blood because it contains lycopene. This study aims to determine the effect of tomato juice (Solanum lycopersicum) on blood triglyceride levels in the wistar strain of male Rattus norvegicus induced by alloxan. Methods: 24 were divided into 3 groups, (1) Group K (-) experimental animals without treatment, (2) Group K (+) experimental animals induced by alloxan 150 mg / kgBB, (3) Treatment group K (P) animals tried alloxan induced 150 mg / kg and got 1.75 ml / head of tomato juice. Results: There was a significant difference in mean triglyceride levels between groups K (-) and group K (+). This indicates that the induction of alloxan increases blood triglyceride levels. There were significant differences in the mean triglyceride levels between the K (+) and K (P) groups because tomato juice contained lycopene which could reduce triglyceride synthesis. Conclusions: Tomato juice (solanum lycopersicum) reduced wistar strain male Rattus novergicus triglyceride levels induced by alloxan.

CD36 and DGAT2 facilitates the lipid-lowering effect of chitooligosaccharides via fatty acid intake and triglyceride synthesis signaling

This study examined the impact of chitobiose (GlcN)2 and chitotriose (GlcN)3 on lipid accumulation modification and its inhibitory functionality. (GlcN)2 and (GlcN)3 was found to significantly inhibit the total cholesterol...

Liver X receptor α participates in LPS-induced reduction of triglyceride synthesis in bovine mammary epithelial cells

Lipopolysaccharides (LPS) could induce milk fat depression via regulating the body and blood fat metabolism. However, it is not completely clear how LPS might regulate triglyceride synthesis in dairy cow mammary epithelial cells (DCMECs). DCMECs were isolated and purified from dairy cow mammary tissue and treated with LPS. The level of triglyceride synthesis, the expression and activity of the liver X receptor α (LXRα), enzymes related to de novo fatty acid synthesis, and the expression of the fatty acid transporters were investigated. We found that LPS decreased the level of triglyceride synthesis via a down-regulation of the transcription, translation, and nuclear translocation level of the LXRα. The results also indicated that the transcription level of the LXRα target genes, sterol regulatory element binding protein 1 (SREBP1), fatty acid synthetase (FAS), acetyl-CoA carboxylase-1 (ACC1), were significantly down-regulated in DCMECs after LPS treatment. Our data may provide new insight into the mechanisms of milk fat depression caused by LPS.

Regulation of Signaling and Metabolism by Lipin-mediated Phosphatidic Acid Phosphohydrolase Activity

Phosphatidic acid (PA) is a glycerophospholipid intermediate in the triglyceride synthesis pathway that has incredibly important structural functions as a component of cell membranes and dynamic effects on intracellular and intercellular signaling pathways. Although there are many pathways to synthesize and degrade PA, a family of PA phosphohydrolases (lipin family proteins) that generate diacylglycerol constitute the primary pathway for PA incorporation into triglycerides. Previously, it was believed that the pool of PA used to synthesize triglyceride was distinct, compartmentalized, and did not widely intersect with signaling pathways. However, we now know that modulating the activity of lipin 1 has profound effects on signaling in a variety of cell types. Indeed, in most tissues except adipose tissue, lipin-mediated PA phosphohydrolase activity is far from limiting for normal rates of triglyceride synthesis, but rather impacts critical signaling cascades that control cellular homeostasis. In this review, we will discuss how lipin-mediated control of PA concentrations regulates metabolism and signaling in mammalian organisms.