Department of Internal Medicine (M.K., F.M., H.-U.H., E.S., A.P.), Division of Endocrinology, Diabetology, Angiology, Nephrology, Clinical Chemistry and Pathobiochemistry, University of Tübingen, 72076 Tübingen, Germany; Department of General, Visceral and Transplant Surgery (I.K., A.K.), University of Tübingen, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen (F.M., H.-U.H., E.S., A.P.), 72076 Tübingen, Germany; and German Center for Diabetes Research (DZD) (F.M., H.-U.H., E.S., A.P.), 85764 München-Neuherberg, Germany.
J Clin Endocrinol Metab. 2015 Dec;100(12):E1568-74. doi: 10.1210/jc.2015-2978. Epub 2015 Oct 6.
Previous studies revealed that the common sequence variant I148M in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is associated with liver fat content and liver diseases, but not with insulin resistance. Recent data suggest that the PNPLA3 I148M variant has reduced retinyl-palmitate lipase activity in hepatic stellate cells.
We hypothesized that the PNPLA3 I148M variant is associated with elevated retinyl-palmitate storage in human liver as a potential link to the clinical pathology. Design/Setting and Participants: Using HPLC, we quantified the retinoid metabolites in liver tissue extracts obtained from 42 human subjects, including 13 heterozygous and six homozygous carriers of the minor PNPLA3 I148M variant.
Retinyl-palmitate is elevated in human livers of homozygous PNPLA3 I148M allele carriers Results: The PNPLA3 I148M variant was associated with a significant increase (1.4-fold) in liver fat. The content of retinyl-palmitate was elevated and the ratio of retinol/retinyl-palmitate was reduced in liver extracts obtained from homozygous PNPLA3 I148M minor allele carriers. In a multivariate model including liver fat content, these differences remained significant independent of liver fat content. The content of the minor retinyl-fatty acid esters was similarly increased in homozygous PNPLA3 I148M carriers.
The increased content of hepatic retinyl-palmitate and the reduced ratio of retinol/retinyl-palmitate in PNPLA3 I148M minor allele carriers support in vitro findings of an altered retinyl-palmitate lipase activity. Our results indicate that the PNPLA3 I148M variant is relevant for the retinyl-palmitate content in human liver, providing a possible link to chronic liver disease.
先前的研究表明，载脂蛋白样磷脂酶域包含蛋白 3（PNPLA3）中的常见序列变异 I148M 与肝脂肪含量和肝脏疾病相关，但与胰岛素抵抗无关。最近的数据表明，PNPLA3 I148M 变体在肝星状细胞中具有降低的视黄醇棕榈酸酯脂肪酶活性。
我们假设 PNPLA3 I148M 变体与人类肝脏中视黄醇棕榈酸酯的储存增加有关，这可能是与临床病理学的潜在联系。设计/设置和参与者：使用 HPLC，我们对从 42 名人类受试者获得的肝组织提取物中的类视黄醇代谢物进行了定量，其中包括 13 名杂合子和 6 名纯合子 PNPLA3 I148M 变体的携带者。
PNPLA3 I148M 等位基因纯合子携带者的人肝中视黄醇棕榈酸酯升高。结果：PNPLA3 I148M 变体与肝脂肪显著增加（1.4 倍）相关。从纯合子 PNPLA3 I148M 小等位基因携带者的肝提取物中，视黄醇棕榈酸酯的含量升高，视黄醇/视黄醇棕榈酸酯的比值降低。在包括肝脂肪含量的多变量模型中，这些差异在独立于肝脂肪含量的情况下仍然显著。在纯合子 PNPLA3 I148M 携带者中，少量的视黄醇脂肪酸酯的含量也同样增加。
PNPLA3 I148M 小等位基因携带者肝内视黄醇棕榈酸酯含量增加，视黄醇/视黄醇棕榈酸酯比值降低，支持体外改变视黄醇棕榈酸酯脂肪酶活性的发现。我们的结果表明，PNPLA3 I148M 变体与人类肝脏中的视黄醇棕榈酸酯含量相关，为慢性肝病提供了一个可能的联系。
