Dataset Information

The apolipoprotein C-III (Gln38Lys) variant associated with human hypertriglyceridemia is a gain-of-function mutation.

ABSTRACT: 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 (C3^QK), being a gain-of-function mutation, promotes hepatic VLDL₁ assembly/secretion. To test this hypothesis, we expressed C3^QK in McA-RH7777 cells and apoc3-null mice to contrast its effect with WT apoC-III (C3^WT). In both model systems, C3^QK expression increased the secretion of VLDL₁-TAG (by 230%) under lipid-rich conditions. Metabolic labeling experiments with C3^QK cells showed an increase in de novo lipogenesis (DNL). Fasting plasma concentration of TAG, cholesterol, cholesteryl ester, and FA were increased in C3^QK mice as compared with C3^WT mice. Liver of C3^QK mice also displayed an increase in DNL and expression of lipogenic genes as compared with that in C3^WT mice. These results suggest that C3^QK variant is a gain-of-function mutation that can stimulate VLDL₁ production, through enhanced DNL.

SUBMITTER: Sundaram M

PROVIDER: S-EPMC5665666 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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The apolipoprotein C-III (Gln38Lys) variant associated with human hypertriglyceridemia is a gain-of-function mutation.

Sundaram Meenakshi M Curtis Kaitlin R KR Amir Alipour Mohsen M LeBlond Nicholas D ND Margison Kaitlyn D KD Yaworski Rebecca A RA Parks Robin J RJ McIntyre Adam D AD Hegele Robert A RA Fullerton Morgan D MD Yao Zemin Z

Journal of lipid research 20170908 11

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 ...[more]

PMID: 28887372

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Project description:Prolonged periods of increased physical demands can elicit anabolic tendon adaptations that increase stiffness and mechanical resilience or conversely can lead to pathological processes that deteriorate tendon structural quality with ensuing pain and potential rupture. Although the mechanisms by which tendon mechanical loads regulate tissue adaptation are largely unknown, the ion channel PIEZO1 has been implicated in tendon mechanotransduction, with human carriers of the PIEZO1 gain-of-function variant E756del displaying improved dynamic vertical jump performance compared with noncarriers. Here, we sought to examine whether increased tendon stiffness in humans could explain this increased performance. We assessed tendon morphological and mechanical properties with ultrasound-based techniques in 77 participants of Middle- and West-African descent, and we measured their vertical jumping performance to assess potential functional consequences in the context of high tendon strain-rate loading. Carrying the E756del gene variant (n = 30) was associated with 46.3 ± 68.3% (P = 0.002) and 45.6 ± 69.2% (P < 0.001) higher patellar tendon stiffness and Young's modulus compared with noncarrying controls, respectively. Although these tissue level measures strongly corroborate the initial postulate that PIEZO1 plays an integral part in regulating tendon material properties and stiffness in humans, we found no detectable correlation between tendon stiffness and jumping performance in the tested population that comprised individuals of highly diverse physical fitness level, dexterity, and jumping ability.NEW & NOTEWORTHY The E756del gene variant causes overactivity of the mechanosensitive membrane channel PIEZO1 and is suspected to upregulate tendon collagen cross linking. In human carriers of E756del, we found increased patellar tendon stiffness but similar tendon lengths and cross-sectional areas, directly supporting the premise that PIEZO1 regulates human tendon stiffness at the level of tissue material properties.

Dataset Information

The apolipoprotein C-III (Gln38Lys) variant associated with human hypertriglyceridemia is a gain-of-function mutation.

Publications

The apolipoprotein C-III (Gln38Lys) variant associated with human hypertriglyceridemia is a gain-of-function mutation.

Similar Datasets

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