R. Cox

Bio: R. Cox is an academic researcher from Colorado State University. The author has contributed to research in topics: Lactacystin & Insulin resistance. The author has an hindex of 1, co-authored 1 publications receiving 37 citations.

Fatty acids regulate CREBh via transcriptional mechanisms that are dependent on proteasome activity and insulin

Abstract: Excess fatty acids are closely associated with metabolic dysfunction. The deleterious effects of fatty acids relate, in part, to their ability to up-regulate pro-inflammatory cytokines and propagate a state of systemic inflammation. CREBh is a recently identified transcription factor that appears to be required for hepatic synthesis of C-reactive protein. Recent data suggest that fatty acids can up-regulate CREBh, thus establishing a potential molecular link between fatty acids and inflammation. The aim of this study was to examine the nature and mechanisms of fatty acid-mediated regulation of CREBh. H4IIE liver cells were incubated in the absence or presence of varying concentrations (50-500 μM) of albumin-bound, long-chain saturated (palmitate, stearate) or unsaturated (oleate, linoleate) fatty acids (1-16 h). All fatty acids significantly increased CREBh gene expression via transcriptional mechanisms, at concentrations as low as 50 μM. Palmitate- or oleate-mediated up-regulation of CREBh was not inhibited by triacsin C, an inhibitor of long-chain fatty acyl CoA synthetase, or by the PPARα antagonist, MK886. Inhibition of proteasome activity with MG132 or lactacystin, or inclusion of insulin reduced palmitate- and oleate-mediated increases in CREBh mRNA. Finally, we examined fatty acid regulation of CREBh in vivo. Male Wistar rats were exposed to a 4-h pancreatic clamp combined with infusion of saline or a mixed lipid emulsion. CREBh mRNA and protein were significantly increased in rats exposed to the lipid infusion compared to the saline group. Collectively, these results may have important implications for metabolic diseases characterized by excess fatty acids, insulin resistance, and inflammation.

Nutritional Metabolomics: Progress in Addressing Complexity in Diet and Health

Abstract: Nutritional metabolomics is rapidly maturing to use small-molecule chemical profiling to support integration of diet and nutrition in complex biosystems research. These developments are critical to facilitate transition of nutritional sciences from population-based to individual-based criteria for nutritional research, assessment, and management. This review addresses progress in making these approaches manageable for nutrition research. Important concept developments concerning the exposome, predictive health, and complex pathobiology serve to emphasize the central role of diet and nutrition in integrated biosystems models of health and disease. Improved analytic tools and databases for targeted and nontargeted metabolic profiling, along with bioinformatics, pathway mapping, and computational modeling, are now used for nutrition research on diet, metabolism, microbiome, and health associations. These new developments enable metabolome-wide association studies (MWAS) and provide a foundation for nutritional metabolomics, along with genomics, epigenomics, and health phenotyping, to support the integrated models required for personalized diet and nutrition forecasting.

Endoplasmic Reticulum Stress in Nonalcoholic Fatty Liver Disease

Abstract: The underlying causes of nonalcoholic fatty liver disease are unclear, although recent evidence has implicated the endoplasmic reticulum in both the development of steatosis and progression to nonalcoholic steatohepatitis. Disruption of endoplasmic reticulum homeostasis, often termed ER stress, has been observed in liver and adipose tissue of humans with nonalcoholic fatty liver disease and/or obesity. Importantly, the signaling pathway activated by disruption of endoplasmic reticulum homeostasis, the unfolded protein response, has been linked to lipid and membrane biosynthesis, insulin action, inflammation, and apoptosis. Therefore, understanding the mechanisms that disrupt endoplasmic reticulum homeostasis in nonalcoholic fatty liver disease and the role of the unfolded protein response in the broader context of chronic, metabolic diseases have become topics of intense investigation. The present review examines the endoplasmic reticulum and the unfolded protein response in the context of nonalcoholic fatty liver disease.

Fatty acids and the endoplasmic reticulum in nonalcoholic fatty liver disease.

Abstract: Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning public health concern in westernized nations. The obesity-related disorder is associated with an increased risk of cardiovascular disease, type 2 diabetes and liver failure. Although the underlying pathogenesis of NAFLD is unclear, increasing evidence suggests that excess saturated fatty acids presented to or stored within the liver may play a role in both the development and progression of the disorder. A putative mechanism linking saturated fatty acids to NAFLD may be endoplasmic reticulum (ER) stress. Specifically, excess saturated fatty acids may induce an ER stress response that, if left unabated, can activate stress signaling pathways, cause hepatocyte cell death, and eventually lead to liver dysfunction. In the current review we discuss the involvement of saturated fatty acids in the pathogenesis of NAFLD with particular emphasis on the role of ER stress.