The apolipoprotein C-III (Gln38Lys) variant associated with human hypertriglyceridemia is a gain-of-function mutation[S]
| Autor: | Adam D. McIntyre, Robin J. Parks, Morgan D. Fullerton, Robert A. Hegele, Kaitlin R. Curtis, Meenakshi Sundaram, Zemin Yao, Kaitlyn D. Margison, Nicholas D. LeBlond, Rebecca A. Yaworski, Mohsen Amir Alipour |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Very low-density lipoprotein QD415-436 030204 cardiovascular system & hematology Biochemistry Cell Line 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Endocrinology Internal medicine medicine Animals Humans Hypertriglyceridemia Apolipoprotein C-III Chemistry Cholesterol Lipogenesis lipogenic gene expression Cell Biology medicine.disease 030104 developmental biology de novo lipogenesis Gene Expression Regulation Cell culture Gain of Function Mutation Cholesteryl ester lipids (amino acids peptides and proteins) Apolipoprotein C2 Patient-Oriented and Epidemiological Research Lipoproteins HDL VLDL Gene Deletion |
| Zdroj: | Journal of Lipid Research, Vol 58, Iss 11, Pp 2188-2196 (2017) |
| Popis: | Recent cell culture and animal studies have suggested that expression of human apo C-III in the liver has a profound impact on the triacylglycerol (TAG)-rich VLDL1 production under lipid-rich conditions. The apoC-III Gln38Lys variant was identified in subjects of Mexican origin with moderate hypertriglyceridemia. We postulated that Gln38Lys (C3QK), being a gain-of-function mutation, promotes hepatic VLDL1 assembly/secretion. To test this hypothesis, we expressed C3QK in McA-RH7777 cells and apoc3-null mice to contrast its effect with WT apoC-III (C3WT). In both model systems, C3QK expression increased the secretion of VLDL1-TAG (by 230%) under lipid-rich conditions. Metabolic labeling experiments with C3QK cells showed an increase in de novo lipogenesis (DNL). Fasting plasma concentration of TAG, cholesterol, cholesteryl ester, and FA were increased in C3QK mice as compared with C3WT mice. Liver of C3QK mice also displayed an increase in DNL and expression of lipogenic genes as compared with that in C3WT mice. These results suggest that C3QK variant is a gain-of-function mutation that can stimulate VLDL1 production, through enhanced DNL. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|