School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Int J Mol Sci. 2021 Apr 13;22(8):4001. doi: 10.3390/ijms22084001.
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.
通过 GPR109a 信号传递，假定的内源性配体β-OH 丁酸的受体，抑制脂肪组织脂肪分解。烟酸，一种抗动脉粥样硬化药物，可诱导胰岛素抵抗，以 nM 浓度激活 GPR109a。GPR109a 对于烟酸改善血清脂质谱不是必需的。为了更好地理解 GPR109a 信号在调节葡萄糖和脂质代谢中的作用，我们在生理状态下用生理盐水或烟酸处理 GPR109a 野生型（+/+）和敲除（-/-）小鼠，生理状态下内源性配体β-OH 丁酸的浓度低（自由进食）或高（16 小时禁食）。在进食状态下，烟酸增加了载脂蛋白-A1 mRNA 的表达，并降低了固醇调节元件结合蛋白 1 mRNA 的表达，与基因型无关，这表明烟酸增加高密度脂蛋白（HDL）的产生和限制脂肪生成基因转录上调的可能是 GPR109a 独立机制。烟酸降低了 GPR109a +/+ 和-/- 小鼠禁食血清中非酯化脂肪酸的浓度。烟酸独立于 GPR109a 的表达，减弱了快速诱导的肝甘油三酯积累和过氧化物酶体增殖物激活受体α mRNA 的表达。尽管不受烟酸处理的影响，但禁食血清 HDL 浓度在 GPR109a 敲除小鼠中较低。令人惊讶的是，GPR109a 敲除小鼠在进食或禁食状态下的葡萄糖或脂质稳态或肝基因表达均不受影响。反过来，GPR109a 似乎对于禁食生酮状态或烟酸的急性作用的代谢反应不是必需的。
