Biology subjects

Gemmink, A.

Publications and source records attributed to Gemmink, A..

3 recordsLinked to original sources

bioRxiv2024

ATGL-mediated lipolysis is essential for myocellular mitochondrial function and augments PPARδ-induced improvements in mitochondrial respiration

Defects in ATGL-mediated myocellular LD lipolysis results in mitochondrial dysfunction of unknown origin, which can be rescued by PPAR agonists. Here we examine whether ATGL-mediated lipolysis is required to maintain mitochondrial network connectivity and function. Moreover, we explored if the functional implications of ATGL deficiency for mitochondrial network dynamics and function can be alleviated by promoting PPAR and/or PPAR{delta} transcriptional activity. To this end, we cultured human primary myotubes from patients with neutral lipid storage disease with myopathy (NLSDM), a rare metabolic disorder caused by a mutation in the PNPLA2 gene. These myotubes possess dysfunctional ATGL and compromised LD lipolysis. In addition, mitochondria-LD contacts, mitochondrial network dynamics, and TMRM intensity were abrogated. Using a humanized ATGL inhibitor in myotubes cultured form healthy donors, revealed similar results. Upon stimulating PPAR{delta} transcriptional activity, mitochondrial respiration improved by more than 50% in human primary myotubes from healthy lean individuals. This increase in respiration was dampened in myotubes with dysfunctional ATGL. Stimulation of PPAR{delta} transcriptional activity had no effect on mitochondria-LD contacts, mitochondrial network dynamics, and TMRM intensity. Our results demonstrate that dysfunctional ATGL results in compromised mitochondrial-LD contacts and mitochondrial dynamics, and that functional ATGL is required to improve mitochondrial respiratory capacity upon stimulation of PPAR{delta} transcriptional activity.

physiology↗

bioRxiv2021

Type II muscle fibre properties are not associated with balance recovery following large perturbations during walking in young and older adults

Falls among older adults are often attributed to declining muscle strength with ageing. Associations between muscle strength and balance control have been reported, but the evidence for, and key mechanisms of resistance exercise in fall prevention are unclear. No studies have directly examined the relationship between muscle fibre characteristics and reactive balance control. Here, we address whether or not Type II muscle fibre characteristics associate with reactive balance during walking in young and older adults with varying muscle fibre type composition. We analyse muscle biopsy-derived fibre characteristics and stability during a treadmill-based walking perturbation (trip-like) task of healthy young adults, healthy, normally active older adults, trained older adults and physically impaired older adults. We find no significant associations between Type II muscle fibre properties and reactive balance during walking, indicating that practitioners and researchers should consider more than just the muscle tissue properties when assessing and intervening on fall risk.

physiology↗

bioRxiv2020

Hypoxia-inducible lipid droplet-associated interacts with DGAT1 to promote lipid storage in hepatocytes

Lipid droplets (LD) are dynamic organelles that can expand and shrink, driven by fluctuations in the rate of triglyceride synthesis and degradation. Triglyceride synthesis, storage in LD, and degradation are governed by a complex set of LD-associated proteins. One of these LD-associated proteins, hypoxia-inducible lipid droplet-associated (HILPDA), was found to impair LD breakdown by inhibiting adipose triglyceride lipase. Here we characterized the physiological role and mechanism of action of HILPDA in hepatocytes. Expression of HILPDA was induced by fatty acids in several hepatoma cell lines. Hepatocyte-specific deficiency of HILPDA in mice modestly but significantly reduced hepatic triglycerides in mice with non-alcoholic fatty liver disease. Similarly, deficiency of HILPDA in mouse precision-cut liver slices and primary hepatocytes reduced lipid storage and accumulation of fluorescently-labelled fatty acids in LD, respectively, which was independent of adipose triglyceride lipase. Fluorescence microscopy showed that HILPDA partly colocalizes with LD and with the endoplasmic reticulum, is especially abundant in perinuclear areas, and mainly associates with newly added fatty acids. Real-time fluorescence live-cell imaging further revealed that HILPDA preferentially localizes to LD that are being remodelled. Mechanistically, HILPDA overexpression increased lipid storage in human hepatoma cells concomitant with an increase in DGAT activity and DGAT1 protein levels. Finally, confocal microscopy and Forster resonance energy transfer-fluorescence lifetime imaging microscopy analysis indicated that HILPDA colocalizes and physically interacts with DGAT1. Overall, our data indicate that HILPDA physically interacts with DGAT1 and increases DGAT activity. These findings suggest a novel mechanism in hepatocytes that links elevated fatty acid levels to stimulation of triglyceride synthesis and storage.

biochemistry↗