Free fatty acids (FFAs) are implicated in the pathogenesis of metabolic diseases that include obesity, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD). FFAs serve as ligands for free fatty acid receptors (FFARs) that belong to the family of rhodopsin-like G protein-coupled receptors (GPCRs) and are expressed throughout the body to maintain energy homeostasis under changing nutritional conditions. Free fatty acid receptor 4 (FFAR4), also known as G protein-coupled receptor 120 (GPR120), is a long-chain fatty acid receptor highly expressed in adipocytes, endothelial cells, and macrophages. Activation of FFAR4 helps maintain metabolic homeostasis by regulating adipogenesis, insulin sensitivity, and inflammation. Furthermore, dysfunction of FFAR4 is associated with insulin resistance, obesity, and eccentric remodeling in both humans and mice, making FFAR4 an attractive therapeutic target for treating or preventing metabolic diseases. While much of the previous literature on FFAR4 has focused on its role in obesity and diabetes, recent studies have demonstrated that FFAR4 may also play an important role in the development of atherosclerosis and CVD. Most notably, FFAR4 activation reduces monocyte-endothelial cell interaction, enhances cholesterol efflux from macrophages, reduces lesion size in atherogenic mouse models, and stimulates oxylipin production in myocytes that functions in a feed-forward cardioprotective mechanism. This review will focus on the role of FFAR4 in metabolic diseases and highlights an underappreciated role of FFAR4 in the development of atherosclerosis and CVD.

No difference was found between groups of senescent subjects and younger adults in the control of skin temperature, heat radiation and transcutaneous oxygen pressure. Although capillary numbers decline in elderly skin, transcutaneous oxygen pressure at 43 degrees C in elderly skin is no lower than in young subjects. Topical tretinoin (0.05%) increases heat radiation from the skin, but there is no correlation with an improvement in superficial wrinkles. No conclusion is possible regarding the effects of topical tretinoin on transcutaneous oxygen diffusion due to a wide variability in results; sometimes it is increased and sometimes it is decreased. In different regions of the skin, such as the face and thigh, increased skin radiation and skin contact temperature are not associated with increased transcutaneous oxygen diffusion.

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Fumarase C (FumC) catalyzes the reversible conversion of fumarate to S‐malate. Previous structural investigations within the superfamily have reported a dynamic structural segment, termed the SS Loop. To date, active‐site asymmetry has raised the question of how SS Loop placement affects participation of key residues during the reaction. Herein, we report structural and kinetic analyses from Escherichia coli FumC variants to understand the contribution of SS Loop residues S318, K324, and N326. High‐resolution X‐ray crystallographic results reveal three distinct FumC active‐site conformations; disordered‐open, ordered‐open, and the newly discovered ordered‐closed. Surprisingly, each SS Loop variant has unaffected Michaelis constants coupled to reductions in turnover number. Based upon our structural and functional analyses, we propose structural and catalytic roles for each of the aforementioned residues.

The protein structure and function paradigm, a foundational tenet of biomolecular science, underlies many infectious diseases. Hemolysin A (HpmA), a hemolytic protein produced by Proteus mirabilis, was used as a model to investigate the protein structure‐function paradigm. HpmA is a member of the two‐partner secretion (TPS) pathway, which is used by gram‐negative bacteria to export predominantly virulent proteins outside of the cell. Through this mechanism, the A‐component (HpmA) is translocated, folded, and activated by its cognate B‐component in the absence of high‐energy bond and electrochemical gradient dependency. All TpsA components are relatively large and can be further divided into two domains, the two‐partner secretion domain and the functional domain. Universally, all known TPS domains harbor a right‐handed, parallel β‐helix architecture and are essential for cognate TpsB‐dependent recognition and secretion. Conversely, functional domains provide TpsA diversification including, cytolysis, host cell adhesion, contact‐growth inhibition, and iron sequestration. A truncated version of hemolysin A (HpmA265) was implemented to define the contributions of the TPS domain toward TpsA structure and function. Recently, our group has further dissected HpmA265 into three sequentially folded structural units termed the polar core, non‐polar core, and carboxy‐terminal subdomains. This research project aims to expand upon our recent results and structurally map the role of the nonpolar core during TPS domain dependent secretion, folding and function. Specifically, residues within the non‐polar core subdomain have been selectively targeted and modified. The structural and functional effects of these site‐selective modifications have been evaluated via chemical denaturation, protease sensitivity and hemolytic assays. Each site‐selective alteration selectively shifts the unfolding transitions attributed to the non‐polar core and carboxy‐terminal subdomain, while leaving the polar core transition unaffected. Furthermore, non‐polar core subdomain destabilization differentially alters secretion levels, while leaving hemolytic activity unaffected. More broadly, these results further define β‐helix TPS domain contribution during gram‐negative bacterial infections like whooping cough, meningitis, and urinary tract infections.Support or Funding InformationFunding for this research was provided by: University Wisconsin – La Crosse Faculty Research Grant Program (TMW) and University Wisconsin – La Crosse Undergraduate Research and Creativity Grant Program (GMS).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.