Hypoxia Restrains Lipid Utilization via Protein Kinase A and Adipose Triglyceride Lipase Downregulation through Hypoxia-Inducible Factor

Abstract

Oxygen is a key molecule for efficient energy production in living organisms. Although aerobic organisms have adaptive processes to survive in low-oxygen environments, it is poorly understood how lipolysis, the first step of energy production from stored lipid metabolites, would be modulated during hypoxia. Here, we demonstrate that fasting-induced lipolysis is downregulated by hypoxia through the hypoxia-inducible factor (HIF) signaling pathway. In Caenorhabditis elegans and mammalian adipocytes, hypoxia suppressed protein kinase A (PKA)-stimulated lipolysis, which is evolutionarily well conserved. During hypoxia, the levels of PKA activity and adipose triglyceride lipase (ATGL) protein were downregulated, resulting in attenuated fasting-induced lipolysis. In worms, HIF stabilization was sufficient to moderate the suppressive effect of hypoxia on lipolysis through ATGL and PKA inhibition. These data suggest that HIF activation under hypoxia plays key roles in the suppression of lipolysis, which might preserve energy resources in both C. elegans and mammalian adipocytes.

Insulin negatively regulates dedifferentiation of mouse adipocytes in vitro

“…This indicates that intact insulin/AKT signalling plays an important role in negatively controlling the dedifferentiation of adipogenicdifferentiated cells. ATGL is expressed predominantly in adipose tissue [30]. In the present study, as expected, ATGL was upregulated upon dedifferentiation, reached a peak at time point of DD3 in all groups, but it was decreased at the late phase of dedifferentiation (DD8).…”

“…In the present study, as expected, ATGL was upregulated upon dedifferentiation, reached a peak at time point of DD3 in all groups, but it was decreased at the late phase of dedifferentiation (DD8). This result indicates that increased lipolysis is related to the hypofunction of insulin signalling, resulting in up-regulated lipolytic factors such as ATGL, and down-regulated adipogenic factors, eventually promoting the metabolism of intracellular lipids and adipocyte dedifferentiation [30,31].…”

The Role of Reversible Protein Phosphorylation in Regulation of the Mitochondrial Electron Transport System During Hypoxia and Reoxygenation Stress in Marine Bivalves

“…Earlier studies in humans and model organisms demonstrated an important role of PKA and PKC in responses to H/R stress such as occurs during ischemia-reperfusion (Armstrong, 2004;Sanada et al, 2004;Hüttemann et al, 2012). In hypoxiasensitive terrestrial mammals, PKA and PKC are activated by hypoxia (Srinivasan et al, 2013;Gozal et al, 2017;Lucia et al, 2020), whereas in a nematode Caenorhabditis elegans, hypoxia suppresses PKA activity (Han et al, 2019). Our present study showed a strong species-specific modulation of the protein kinase activities by H/R stress in marine bivalves ranging from no change (except for a transient decrease in PKC during shortterm hypoxia) in M. edulis, an increase during hypoxia and 1 26 1 3 5 8 2 3 2 31 50 2 54 188 ND1 5 1 7 10 12 35 ND2 1 1 1 5 10 8 26 ND3 2 1 3 3 9 ND4 6 1 2 2 1 1 7 10 5 35 ND4L 1 1 1 3 2 1 9 ND5 8 2 3 1 2 2 6 12 1 19 56 ND6 3 1 1 3 3 1 6 18 Names of the kinases are given in the head row of the table.…”

Hypoxia-Inducible Factors and the Regulation of Lipid Metabolism

“…A connection between HIF-induced TG synthesis and cell proliferation is supported by metabolic profiling analysis of cancer cells kept under hypoxia, which has shown that the concentration of TAGs and derivative phospholipids PC and PE is substantially increased in a HIF-1α-dependent manner [77]. It has to be pointed out that, in many cancer types, silencing of HIFs or interfering with the expression of its target genes required for lipid accumulation, results in reduction of proliferation potential and chemoresistance under hypoxia [49,55,57,59,62,63,65,68,70,78,79]. Moreover, the overexpression of HIF-regulated genes involved in lipid metabolism has been correlated with malignant subtypes of human cancers or poor patient prognosis [70,79].…”