Dataset Information

The response to fasting and refeeding reveals functional regulation of lipoprotein lipase proteoforms

ABSTRACT: Lipoprotein lipase (LPL) is responsible for the intravascular catabolism of triglyceride-rich lipoproteins and plays a central role in whole-body energy balance and lipid homeostasis. As such, LPL is subject to tissue-specific regulation in different physiological conditions, but the mechanisms of this regulation remain incompletely characterized. Previous work revealed that LPL comprises a set of proteoforms with different isoelectric points, but their regulation and functional significance have not been studied thus far. Here we studied the distribution of LPL proteoforms in different rat tissues and their regulation under physiological conditions. First, analysis by two-dimensional electrophoresis and Western blot showed different patterns of LPL proteoforms (i.e., different pI or relative abundance of LPL proteoforms) in different rat tissues under basal conditions, which could be related to the tissue-specific regulation of the enzyme. Next, the comparison of LPL proteoforms from heart and brown adipose tissue between adults and 15-day-old rat pups, two conditions with minimal regulation of LPL in these tissues, yielded virtually the same tissue-specific patterns of LPL proteoforms. In contrast, the pronounced down-regulation of LPL activity observed in white adipose tissue during fasting is accompanied by a prominent reconfiguration of the LPL proteoform pattern. Furthermore, refeeding reverts this down-regulation of LPL activity and restores the pattern of LPL proteoforms in this tissue. Importantly, this reversible proteoform-specific regulation during fasting and refeeding indicates that LPL proteoforms are functionally diverse. Further investigation of potential differences in the functional properties of LPL proteoforms showed that all proteoforms exhibit lipolytic activity and have similar heparin-binding affinity, although other functional aspects remain to be investigated. Overall, this study demonstrates the ubiquity, differential distribution and specific regulation of LPL proteoforms in rat tissues and underscores the need to consider the existence of LPL proteoforms for a complete understanding of LPL regulation under physiological conditions.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Macaca Fascicularis (crab-eating Macaque) (cynomolgus Monkey)

TISSUE(S): Blood

SUBMITTER: Montserrat Carrascal

LAB HEAD: M.Dolores López-Tejero

PROVIDER: PXD043704 | Pride | 2024-01-26

REPOSITORIES: Pride

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Publications

The response to fasting and refeeding reveals functional regulation of lipoprotein lipase proteoforms.

Carulla Pere P Badia-Villanueva Míriam M Civit Sergi S Carrascal Montserrat M Abian Joaquin J Ricart-Jané David D Llobera Miquel M Casanovas Albert A López-Tejero M Dolores MD

Frontiers in physiology 20231016

Lipoprotein lipase (LPL) is responsible for the intravascular catabolism of triglyceride-rich lipoproteins and plays a central role in whole-body energy balance and lipid homeostasis. As such, LPL is subject to tissue-specific regulation in different physiological conditions, but the mechanisms of this regulation remain incompletely characterized. Previous work revealed that LPL comprises a set of proteoforms with different isoelectric points, but their regulation and functional significance hav ...[more]

PMID: 37916217

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Project description:Regulation of the thermogenic response by brown adipose tissue (BAT) is an important mechanism in the basic biology and treatment of obesity and diabetes. Consensus transcriptional regulatory analysis of a publicly-available RNA-seq dataset uncovered a large number of nodes representing epigenetic modifiers that were altered in BAT in response to chronic thermogenic activation. Thus, we hypothesized that chronic activation of BAT results in epigenetic modifications of DNA and histones that affect the tissue function. To test our hypothesis, wildtype male C57BL/6J mice were housed under chronic conditions of thermoneutral temperature (TN, 28.8°C), mild cold/room temperature (RT, 22°C), or severe cold (SC, 8°C). Reduced representation bisulfite sequencing (RRBS) revealed a marked decrease in methylation of promoters and intragenic regions in BAT genomic DNA in response to varying degrees of chronic cold exposure. Integration of our RRBS and the publicly available RNA-Seq dataset suggested a role for epigenetic modification of DNA in gene regulation in response to cold. To analyze histone modifications, we developed a robust method for the isolation and quantitation of histone proteoforms, which enabled the first comparison of histone H3.2 and H4 proteoforms in BAT. We report distinct on/off histone signals that are observed with histone H3.2 in BAT, but not in the liver, when mice are acclimated to severe cold in comparison with mild cold. Specifically, we observe a larger percentage of histone H3.2 with the K9 dimethylation mark coupled with K36 mono- or di-methylation and K23 acetylation, suggesting strong repression of previously active chromatin. Taken together, our results provide novel findings supporting global epigenetic modification in murine BAT in response to varying degrees of chronic cold stimuli and establish a methodology to quantitatively study histones in BAT, allowing for direct comparisons to decipher mechanistic changes during the thermogenic response.

Dataset Information

The response to fasting and refeeding reveals functional regulation of lipoprotein lipase proteoforms

Publications

The response to fasting and refeeding reveals functional regulation of lipoprotein lipase proteoforms.

Similar Datasets

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