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.

Keywords: GPR109a; liver; metabolic homeostasis; niacin; β-OH butyrate.

Figure 1

Effect of niacin on glucose homeostasis in fed GPR109a +/+ and −/− mice. Hepatic (A) glycogen (mg/g liver tissue), serum (B) glucose (mg/dL), (C) insulin (ng/mL), and (D) glucose:insulin ratio. Direct comparisons were made between injection treatment within genotype. (E) Glucose tolerance test in 4-h fasted mice. (F) Glucose tolerance test area under the curve. (G) Glucose stimulated serum insulin. Bars were analyzed by a two-sided unpaired t-test. NS = non-significant; p > 0.05; PBS = phosphate-buffered saline. Numbers inside bars denote the n per group.

Figure 2

Effect of niacin on lipid and cholesterol homeostasis in fed GPR109a +/+ and −/− mice. Serum (A) non-esterified fatty acids (NEFA; µM) and (B) triacylglycerol (TAG; mg/dL). Hepatic (C) non-esterified fatty acids (NEFA; µmol/g liver tissue) and (D) triacylglycerol (TAG; mg/g liver tissue). Serum (E) β-OH butyrate (µM), (F) low-density lipoprotein (LDL; mg/dL), and (G) high-density lipoprotein (HDL; mg/dL). Direct comparisons were made between injection treatments within genotype. NS = non-significant; p > 0.05; PBS = phosphate-buffered saline. Numbers inside bars denote the n per group.

Figure 3

Effect of niacin on hepatic gene expression in fed GPR109a +/+ and −/− mice. Hepatic (A) PPARα mRNA expression, (B) PEPCK mRNA expression, (C) UCP2 mRNA expression, (D) HMGCS2 mRNA expression, (E) CPT1 mRNA expression, (F) CPT1 protein expression, (G) HMGCS1 mRNA expression, (H) HMGCR mRNA expression, (I) Apo-A1 mRNA expression, (J) SREBP1 mRNA expression, and (K) SREBP2 mRNA expression. Direct comparisons were made between injection treatments within genotypes. NS = non-significant; p > 0.05; PBS = phosphate-buffered saline. Numbers inside bars denote the n per group.

Figure 4

Effect of niacin on glucose homeostasis in 16 h fasted GPR109a +/+ and −/− mice. Hepatic (A) glycogen (mg/g liver tissue), serum (B) glucose (mg/dL), (C) insulin (ng/mL), and (D) glucose:insulin ratio. Direct comparisons were made between injection treatment within genotype. NS = non-significant; p > 0.05; PBS = phosphate buffered saline. Numbers inside bars denote the n per group.

Figure 5

Effect of niacin on lipid and cholesterol homeostasis in 16 h fasted GPR109a +/+ and −/− mice. Serum (A) non-esterified fatty acids (NEFA; µM) and (B) triacylglycerol (TAG; mg/dL). Hepatic (C) non-esterified fatty acids (NEFA; µmol/g liver tissue) and (D) triacylglycerol (TAG; mg/g liver tissue). Serum (E) β-OH butyrate (µM), (F) low-density lipoprotein (LDL; mg/dL), and (G) high-density lipoprotein (HDL; mg/dL). Direct comparisons were made between injection treatments within genotypes. NS = non-significant; p > 0.05; PBS = phosphate-buffered saline. Numbers inside bars denote the n per group.

Figure 6

Effect of niacin on hepatic gene expression in 16 h fasted GPR109a +/+ and −/− mice. Hepatic (A) PPARα mRNA expression, (B) PEPCK mRNA expression, (C) UCP2 mRNA expression, (D) HMGCS2 mRNA expression, and (E) CPT1 mRNA expression, (F) CPT1 protein expression, (G) HMGCS1 mRNA expression, (H) HMGCR mRNA expression, (I) Apo-A1 mRNA expression, (J) SREBP1 mRNA expression, and (K) SREBP2 mRNA expression. Direct comparisons were made between injection treatments within genotypes. NS = non-significant; p > 0.05; PBS = phosphate-buffered saline. Numbers inside bars denote the n per group.