Abstract
p53 is known to modulate metabolism and FDXR is required for steroidogenesis. Given that FDXR is a target/regulator of p53, the FDXR–p53 axis may play a unique role in lipid metabolism. Here, we found that expression of ABCA1, a cholesterol-efflux pump, was suppressed by loss of FDXR and/or p53, leading to activation of master lipogenic regulators SREBP1/2. Accordingly, lipid droplets, cholesterol, and triglycerides were increased by loss of FDXR or p53, which were further increased by loss of both FDXR and p53. To explore the biological significance of the FDXR–p53 axis, we generated a cohort of mice deficient in Fdxr and/or Trp53. We found that Fdxr+/−, Trp53+/−, and Fdxr+/−;Trp53+/− mice had a short life span and were prone to spontaneous tumors and liver steatosis. Moreover, the levels of serum cholesterol and triglycerides were significantly increased in Fdxr+/− and Trp53+/− mice, which were further increased in Fdxr+/−;Trp53+/− mice. Interestingly, loss of Fdxr but not p53 led to accumulation of serum low-density lipoprotein. Together, our findings reveal that the FDXR–p53 axis plays a critical role in lipid homeostasis and tumor suppression.
Highlights
Lipids are essential for life and have many functions, including energy storage, membrane building, and signal transduction [1]
Loss of ferredoxin reductase (FDXR) and/or p53 leads to activation of SREBP1/2 and high levels of serum cholesterol, triglycerides, and lowdensity lipoprotein (LDL) in mice We showed above that following activation of SREBP1/2, intracellular lipid droplets, cholesterol, and triglycerides were increased in MEFs, HepG2, and Hep3B cells (Figs. 1–2 and Supplementary Fig. S3)
Biochemically, FDXR is postulated to regulate lipid metabolism through mitochondrial P450 systems for cholesterol side-chain cleavage and hydroxylation of sterol [38, 55,56,57,58,59,60]. It is not clear whether alteration of FDXR activity would lead to aberrant lipid metabolism in vivo
Summary
Lipids are essential for life and have many functions, including energy storage, membrane building, and signal transduction [1]. Multiple pathways to increase intracellular lipid have been observed in cancers, including increased uptake of extracellular cholesterol through LDL receptor [13,14,15], decreased expression of ATP-binding cassette A1 protein (ABCA1) [14, 16,17,18,19], and aberrant activation of SREBP1/2 [18, 20,21,22]. It is of note that FDXR and p53 are mutually regulated and that the FDXR–p53 axis plays a critical role in iron homeostasis for tumor suppression [40,41,42]. We found that like loss of p53, FDXR deficiency led to increased activation of SREBP1/2 and elevated levels of cellular cholesterol and triglycerides via decreased expression of ABCA1. We found that mice deficient in both Fdxr and Trp had a short life span and were prone to spontaneous tumors, liver steatosis and inflammation, as well as elevated levels of serum cholesterol, triglycerides, and lowdensity lipoprotein
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