Branched Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) Protect against Colitis by Regulating Gut Innate and Adaptive Immune Responses

Abstract

We recently discovered a structurally novel class of endogenous lipids, branched palmitic acid esters of hydroxy stearic acids (PAHSAs), with beneficial metabolic and anti-inflammatory effects. We tested whether PAHSAs protect against colitis, which is a chronic inflammatory disease driven predominantly by defects in the innate mucosal barrier and adaptive immune system. There is an unmet clinical need for safe and well tolerated oral therapeutics with direct anti-inflammatory effects. Wild-type mice were pretreated orally with vehicle or 5-PAHSA (10 mg/kg) and 9-PAHSA (5 mg/kg) once daily for 3 days, followed by 10 days of either 0% or 2% dextran sulfate sodium water with continued vehicle or PAHSA treatment. The colon was collected for histopathology, gene expression, and flow cytometry. Intestinal crypt fractions were prepared for ex vivo bactericidal assays. Bone marrow-derived dendritic cells pretreated with vehicle or PAHSA and splenic CD4 ؉ T cells from syngeneic mice were co-cultured to assess antigen presentation and T cell activation in response to LPS. PAHSA treatment prevented weight loss, improved colitis scores (stool consistency, hematochezia, and mouse appearance), and augmented intestinal crypt Paneth cell bactericidal potency via a mechanism that may involve GPR120. In vitro, PAHSAs attenuated dendritic cell activation and subsequent T cell proliferation and Th1 polarization. The anti-inflammatory effects of PAHSAs in vivo resulted in reduced colonic T cell activation and pro-inflammatory cytokine and chemokine expression. These anti-inflammatory effects appear to be partially GPR120-dependent. We conclude that PAHSA treatment regulates innate and adaptive immune responses to prevent mucosal damage and protect against colitis. Thus, PAHSAs may be a novel treatment for colitis and related inflammation-driven diseases.Lipids have been a rich source of chemical matter for the development of new medicines (1). Endogenous small-molecule metabolites are another class of natural products made within the human body that have important biological activities (2). For example, the discovery and synthesis of prostaglandins revealed their diverse biological roles as autocrine and paracrine mediators in many tissues. This led to their development as therapeutic agents for a variety of indications ranging from vasodilatation to glaucoma treatment (3-6). More recently, compounds that target the sphingosine 1 receptors are emerging as novel therapeutics for autoimmune diseases (7). Thus, the discovery and characterization of bioactive lipids is of fundamental interest with broad impact. We recently discovered a structurally novel class of lipids, branched fatty acid esters of hydroxy fatty acids (FAHFAs), 6 with anti-diabetic and anti-inflammatory properties (8). These lipids are products of endogenous synthesis in mammalian tissues and are also present in food. There are more than 16 FAHFA families, and each family is distinguished by having a different fatty acid and hydroxy fatty acid composition. Furthermor...

Absence of Carbohydrate Response Element Binding Protein in Adipocytes Causes Systemic Insulin Resistance and Impairs Glucose Transport

“…Decreased ChREBP/DNL in adipocytes may also result in lower levels of signaling lipids that could impair Glut4 trafficking as demonstrated by rescue of the glucose transport defect in AdChREBP KO adipocytes with PAHSAs. PAHSAs exert their biological activity by activating G protein-coupled receptors (GPCRs) (Lee et al, 2016; Yore et al, 2014). In particular, PAHSA-induced increase in insulin-stimulated glucose transport is mediated by GPR120.…”

“…Also, we recently identified a class of insulin-sensitizing lipids, branched fatty acid esters of hydroxy fatty acids (FAHFAs) that are regulated by ChREBP (Lee et al, 2016; Yore et al, 2014). Serum and WAT levels of one FAHFA sub-family, palmitic acid hydroxy stearic acid (PAHSA) strongly correlate with insulin sensitivity in humans and rodents.…”

Branched Fatty Acyl Esters of Hydroxyl Fatty Acids (FAHFAs), Appealing Beneficial Endogenous Fat against Obesity and Type‐2 Diabetes

“…FAHFAs decrease T‐cell activation in ulcerative colitis in mice. In fact, 3 days‐oral gavage with 5‐ and 9‐PAHSA delay the onset and attenuate the severity of ulcerative colitis in mice (an intestinal chronic inflammatory disease), and 5‐ and 9‐PAHSA improve the function of Paneth cells (cells secreting antimicrobial peptides allowing the elimination of bacteria having penetrated the mucus layer) while they reduce activation and proliferation of pro‐inflammatory T lymphocytes …”

Stereochemistry of Endogenous Palmitic Acid Ester of 9-Hydroxystearic Acid and Relevance of Absolute Configuration to Regulation

“…7 And other novel FAHFA families with anti-inflammatory activities have recently been discovered. Omega-3 fatty acid FAHFAs, produced after the addition of omega-3-fatty acids to cells, have potent anti-inflammatory activity.…”