Hypoxia-Inducible Factors and the Regulation of Lipid Metabolism

Abstract

Oxygen deprivation or hypoxia characterizes a number of serious pathological conditions and elicits a number of adaptive changes that are mainly mediated at the transcriptional level by the family of hypoxia-inducible factors (HIFs). The HIF target gene repertoire includes genes responsible for the regulation of metabolism, oxygen delivery and cell survival. Although the involvement of HIFs in the regulation of carbohydrate metabolism and the switch to anaerobic glycolysis under hypoxia is well established, their role in the control of lipid anabolism and catabolism remains still relatively obscure. Recent evidence indicates that many aspects of lipid metabolism are modified during hypoxia or in tumor cells in a HIF-dependent manner, contributing significantly to the pathogenesis and/or progression of cancer and metabolic disorders. However, direct transcriptional regulation by HIFs has been only demonstrated in relatively few cases, leaving open the exact and isoform-specific mechanisms that underlie HIF-dependency. This review summarizes the evidence for both direct and indirect roles of HIFs in the regulation of genes involved in lipid metabolism as well as the involvement of HIFs in various diseases as demonstrated by studies with transgenic animal models.

Inhibition of oxygen-sensing prolyl hydroxylases increases lipid accumulation in human primary tubular epithelial cells without inducing ER stress

“…PHDi-induced lipid accumulation in hPTEC was dependent on exogenous FA availability, which might imply that PHDi promoted lipid uptake. The import of extracellular FA into the cell is known to be increased by HIF-dependent upregulation of fatty acid binding proteins (FABP) 3, 4 and 7 (Mylonis et al 2019). Therefore, upregulation of FABP might also have a role in PDH-induced lipid accumulation in hPTEC, which should be investigated in further experiments.…”

“…The role of the HIF pathway in the regulation of renal lipid metabolism has been intensively examined in ccRCC (Mylonis et al 2019). However, beyond tumor models, the effects of HIF on lipid metabolism in the kidney are largely unknown.…”

“…Under hypoxic conditions, HIF promotes cellular FA uptake, synthesis and storage and suppresses FA oxidation in cancer cells (Samanta and Semenza 2018). In several tumor cell lines, various lipid metabolic genes were identified as direct HIF transcriptional targets (Mylonis et al 2019). A Vhl-deficient mouse model resembling characteristics of human clear cell renal cell carcinoma (ccRCC) exhibited lipid accumulation in proximal tubules (Fu et al 2011).…”

Hypertension, but not body mass index, is predictive of increased pancreatic lipid content and islet dysfunction

“…HTN induces vasoconstriction of small vessels and reduced microvascular density, which impairs tissue perfusion . In cultured cells and many organs, including the liver and islets, hypoxia and hypoxia‐inducible factors have been associated with altered lipid metabolism and intracellular lipid droplet accumulation . Several animal and cell culture studies have identified that intracellular lipid storage within islets causes a marked reduction in islet function, through inhibition of insulin production and secretion, as well as cellular toxicity .…”

“…64 In cultured cells and many organs, including the liver and islets, hypoxia and hypoxia-inducible factors have been associated with altered lipid metabolism and intracellular lipid droplet accumulation. [65][66][67][68] Several animal and cell culture studies have identified that intracellular lipid storage within islets causes a marked reduction in islet function, through inhibition of insulin production and secretion, as well as cellular toxicity. [41][42][43][44][45]69,70 Consequently, HTN may contribute to chronic tissue hypoxia resulting in lipid accumulation and islet dysfunction.…”