Lin Y, Vonk R J, Slooff M J, Kuipers F, Smit M J
Groningen Institute for Drug Studies (GIDS), Department of Pediatrics, University Hospital, The Netherlands.
Br J Nutr. 1995 Aug;74(2):197-207. doi: 10.1079/bjn19950123.
Propionate is a short-chain fatty acid formed in the colon and supposedly involved in the cholesterol-lowering effect of soluble fibre. To explore the underlying mechanism(s) of this fibre action, we have used human hepatocytes in primary culture to study the effects of propionate on hepatic lipid synthesis. Initial experiments with mevalonate and mevinolin, a competitive inhibitor of hydroxymethylglutaryl (HMG)-CoA reductase (EC 1.1.1.88) were performed to evaluate basic regulatory mechanisms in these cells; results were compared with those obtained with rat hepatocytes. Incubation for 24 h with mevalonate caused a similar, concentration-dependent inhibition of [14C]acetate incorporation into cholesterol in human and rat hepatocytes. Likewise, mevinolin (100 mumol/l) inhibited the formation of cholesterol from radiolabelled acetate by about 80% in cells from both species. Propionate inhibited cholesterol as well as triacylglycerol synthesis from [14C]acetate with a similar concentration-dependency in rat hepatocytes. Fifty percent inhibition was obtained at a propionate concentration of only 0.1 mmol/l. This propionate-induced inhibition was not affected by a 100-fold excess of unlabelled acetate. Human hepatocytes were much less susceptible in this respect: propionate concentrations of 10-20 mmol/l were required to obtain similar inhibitory effects in these cells, i.e. values greatly exceeding reported portal propionate concentrations in humans. The results suggest the existence of differences in the regulation of hepatic cholesterol (and triacylglycerol) synthesis between human and rat liver cells. These results do not support the hypothesis that the fibre-induced decrease in plasma cholesterol concentration in man is mediated by a direct effect of propionate on hepatic cholesterol synthesis.
丙酸是一种在结肠中形成的短链脂肪酸，据推测它参与了可溶性纤维的降胆固醇作用。为了探究这种纤维作用的潜在机制，我们使用原代培养的人肝细胞来研究丙酸对肝脏脂质合成的影响。最初用甲羟戊酸和洛伐他汀（一种羟甲基戊二酰辅酶A还原酶（EC 1.1.1.88）的竞争性抑制剂）进行实验，以评估这些细胞中的基本调节机制；并将结果与大鼠肝细胞的实验结果进行比较。用甲羟戊酸孵育24小时会导致人和大鼠肝细胞中[14C]乙酸掺入胆固醇的过程受到类似的浓度依赖性抑制。同样，洛伐他汀（100 μmol/l）在两种细胞中均使放射性标记的乙酸合成胆固醇的过程受到约80%的抑制。在大鼠肝细胞中，丙酸抑制了[14C]乙酸合成胆固醇以及三酰甘油，且具有类似的浓度依赖性。仅在丙酸浓度为0.1 mmol/l时就可获得50%的抑制率。这种丙酸诱导的抑制作用不受100倍过量未标记乙酸的影响。在这方面，人肝细胞的敏感性要低得多：需要10 - 20 mmol/l的丙酸浓度才能在这些细胞中获得类似的抑制效果，即该值大大超过了报道的人体门静脉丙酸浓度。结果表明人和大鼠肝细胞在肝脏胆固醇（和三酰甘油）合成调节方面存在差异。这些结果不支持以下假设，即膳食纤维引起的人体血浆胆固醇浓度降低是由丙酸对肝脏胆固醇合成的直接作用介导的。
