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The Role of GPR109a Signaling in Niacin Induced Effects on Fed and Fasted Hepatic Metabolism.

ABSTRACT: Signaling through GPR109a, the putative receptor for the endogenous ligand β-OH butyrate, inhibits adipose tissue lipolysis. Niacin, an anti-atherosclerotic drug that can induce insulin resistance, activates GPR109a at nM concentrations. GPR109a is not essential for niacin to improve serum lipid profiles. To better understand the involvement of GPR109a signaling in regulating glucose and lipid metabolism, we treated GPR109a wild-type (+/+) and knockout (-/-) mice with repeated overnight injections of saline or niacin in physiological states characterized by low (ad libitum fed) or high (16 h fasted) concentrations of the endogenous ligand, β-OH butyrate. In the fed state, niacin increased expression of apolipoprotein-A1 mRNA and decreased sterol regulatory element-binding protein 1 mRNA independent of genotype, suggesting a possible GPR109a independent mechanism by which niacin increases high-density lipoprotein (HDL) production and limits transcriptional upregulation of lipogenic genes. Niacin decreased fasting serum non-esterified fatty acid concentrations in both GPR109a +/+ and -/- mice. Independent of GPR109a expression, niacin blunted fast-induced hepatic triglyceride accumulation and peroxisome proliferator-activated receptor α mRNA expression. Although unaffected by niacin treatment, fasting serum HDL concentrations were lower in GPR109a knockout mice. Surprisingly, GPR109a knockout did not affect glucose or lipid homeostasis or hepatic gene expression in either fed or fasted mice. In turn, GPR109a does not appear to be essential for the metabolic response to the fasting ketogenic state or the acute effects of niacin.

SUBMITTER: Geisler CE

PROVIDER: S-EPMC8069761 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Modulation of HDL metabolism by the niacin receptor GPR109A in mouse hepatocytes.

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| S-EPMC8668869 | biostudies-literature

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| S-EPMC1223972 | biostudies-other

Structural and Energetic Insights Into the Interaction of Niacin With the GPR109A Receptor.

Project description:The transmembrane G-protein coupled receptor GPR109A has been previously shown to function as a receptor for niacin in mediating antilipolytic effects. Although administration of high doses of niacin has shown beneficial effects on lipid metabolism, however, it is often accompanied by disturbing side effects such as flushing, liver damage, glucose intolerance, or gastrointestinal problems. Thus, it is important to understand niacin-GPR109A interactions, which can be beneficial for the development of alternate drugs having antilipolytic effects with less or no side effects. To get into the structural insights on niacin binding to GPR109A, we have performed 100 nanoseconds long all-atom MD simulations of five niacin-GPR109A complexes (automatically docked pose 0, and randomly placed niacin in poses 1 to 4 in the receptor crevice) and analyzed using binding free energy calculations and H-bond analysis. Steered MD simulations were used to get an average force for niacin translocation between the bulk and the external crevice of the wild type and mutant (N86Y, W91 S, S178I, and triple mutant of all three residues) GPR109A receptors, as well as GPR109B (as a control that does not bind niacin). The H-bond analysis revealed that TMH3 residue R111 interacts with niacin in a total of 4 (poses 0 to 3) complexes, while residues C177, S178, and S179 contact niacin in complex pose 4, and all these complexes were energetically stable. According to steered MD simulations, all the GPR109A mutants and GPR109B required greater force than that of wild-type GPR109A to translocate in the external crevice, suggesting increased sterical obstacles. Thus, the residues N86 (at the junction of TMH2/ECL2), W91 (ECL2), R111 (TMH3), and ECL3 residues (C177, S178, S179) play an important role for optimal routing of niacin entry and to bind GPR109A.

| S-EPMC8637708 | biostudies-literature

Glucagon administration in vivo stimulates hepatic RNA and protein breakdown in fed and fasted rats.

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