Regulatory effects of arachidonate 5-lipoxygenase on hepatic microsomal TG transfer protein activity and VLDL-triglyceride and apoB secretion in obese mice

Abstract

As 5-lipoxygenase (5-LO) is an emerging target in obesity and insulin resistance, we have investigated whether this arachidonate pathway is also implicated in the progression of obesity-related fatty liver disease. Our results show that 5-LO activity and 5-LO-derived product levels are significantly elevated in the liver of obese ob/ob mice with respect to wild-type controls. Treatment of ob/ob mice with a selective 5-LO inhibitor exerted a remarkable protection from hepatic steatosis as revealed by decreased oil red-O staining and reduced hepatic triglyceride (TG) concentrations. In addition, 5-LO inhibition in ob/ob mice downregulated genes involved in hepatic fatty acid uptake (i.e., L-FABP and FAT/CD36) and normalized peroxisome proliferatoractivated receptor alpha (PPARa) and acyl-CoA oxidase expression, whereas the expression of lipogenic genes [i.e., fatty acid synthase (FASN) and SREBP-1c] remained unaltered. Furthermore, 5-LO inhibition restored hepatic microsomal TG transfer protein (MTP) activity in parallel with a stimulation of hepatic VLDL-TG and apoB secretion in ob/ob mice. Consistent with these findings, 5-LO products directly inhibited MTP activity and triggered cytosolic TG accumulation in CC-1 cells, a murine hepatocyte cell line. Taken together, these findings identify a novel steatogenic role for 5-LO in the liver through mechanisms involving the regulation of hepatic MTP activity and VLDL-TG and apoB secretion.-

5-Lipoxygenase Activating Protein Signals Adipose Tissue Inflammation and Lipid Dysfunction in Experimental Obesity

“…We should also mention that the levels of 5-LO products in adipose tissue detected in our study by both EIA and RP-HPLC analysis were in the picogram range per milligram of tissue. These levels are similar to those reported previously in other tissues by Zhao et al (33), in mouse aortas (0.3 pg/mg tissue); by Qiu et al (34), in human carotid plaques (2.2 pg/mg tissue); and by López-Parra et al (12), in mouse liver (0.6 pg/mg tissue). These data, together with the finding that nanomolar concentrations of 5-LO products were able to induce NFkB activity and cytokine production (i.e., MCP-1, IL-6, and TNF-a) in adipose tissue, strongly support the concept that 5-LO products, mainly LTB 4 , are involved in the inflammatory state of this tissue in obesity.…”

“…The physiological consequences of these changes in adipose tissue function were corroborated in vivo by the observation that inhibition of the 5-LO pathway reduced circulating FFA concentrations and alleviated insulin resistance and hepatic steatosis in mice with dietary obesity. These findings are consistent with the antisteatotic effects exerted by a 5-LO inhibitor in a murine model of obesity-induced hepatic steatosis (12).…”

“…Optimal cutting temperature-embedded liver samples were cut into 5-mm sections and stained with Oil Red O to evaluate the hepatic lipid content, as previously described (12,17). Briefly, cryosections were fixed in 60% isopropanol for 10 min and stained with 0.3% Oil Red O in 60% isopropanol for 30 min and subsequently washed with 60% isopropanol.…”

“…In addition, 5-LO products have pleiotropic actions on adipose fat accumulation and pancreatic function in mice (10,11). Moreover, we recently identified a novel steatogenic role for 5-LO in the liver of obese ob/ob mice, through mechanisms involving the regulation of hepatic microsomal TG transfer protein activity and very low density lipoprotein-TG and apolipoprotein B secretion (12). However, the potential involvement of the 5-LO pathway in adipose tissue inflammation and adipocyte lipid dysfunction in experimental obesity has not been explored.…”

Proteome analysis of the liver in the Chinese fire-bellied newt Cynops orientalis

“…ECH1 and HADHB were detected in liver mitochondria of many animals (Lomba et al, 2010;Lanaspa et al, 2015). Fatty acid synthase and arachidonate 5-lipoxygenase found in the newt liver are involved in the synthesis of fatty acids (López-Parra et al, 2008). Apolipoprotein B100 (APOB100) is unique in liver, and plays a role in moving cholesterol around the body.…”