Fatty aldehyde dehydrogenase is up‐regulated by polyunsaturated fatty acid via peroxisome proliferator‐activated receptor α and suppresses polyunsaturated fatty acid‐induced endoplasmic reticulum stress

Abstract

Fatty aldehyde dehydrogenase (FALDH; also known as ALDH3A2 or ALDH10) oxidizes medium‐ or long‐chain aliphatic aldehydes. FALDH deficiency in humans is known to be the cause of Sjögren–Larsson syndrome, in which individuals display neurological symptoms and cutaneous abnormality. FALDH‐V, a splice isoform of FALDH, is localized in the peroxisome and contributes to the oxidization of pristanal, an intermediate of the α‐oxidation pathway. FALDH‐N, another splice isoform of FALDH, is induced by peroxisomal proliferator‐activated receptor α ligands, although its activation mechanism has not been clarified. In the present study, we show that transcriptional activation of FALDH is directly regulated by peroxisomal proliferator‐activated receptor α through a direct repeat‐1 site located in the FALDH promoter. In addition, FALDH is efficiently induced by linoleic acid in rat hepatoma Fao cells through transcriptional activation by peroxisomal proliferator‐activated receptor α. Furthermore, ectopic expression of endoplasmic reticulum‐localizing FALDH‐N, but not peroxisome‐localizing FALDH‐V, suppresses endoplasmic reticulum stress caused by linoleic acid in HEK293 cells. These results suggest the autocatalytic nature of the FALDH‐N system against endoplasmic reticulum stress that is induced by polyunsaturated fatty acid; polyunsaturated fatty acid binds to peroxisomal proliferator‐activated receptor α to activate the expression of FALDH‐N, which then detoxifies polyunsaturated fatty acid‐derived fatty aldehydes and protects cells from endoplasmic reticulum stress.

Ketone Body Therapy Protects From Lipotoxicity and Acute Liver Failure Upon Pparα Deficiency

“…Of note, wild-type and Ppar␣-deficient mice fed a normal chow diet displayed significant changes neither in hepatic TG levels (Supplemental Figure 3A), nor in liver ROS, MDA (Supplemental Figure 3, C and D), and Gsta1 mRNA levels (Supplemental Figure 3E). In line with previously published data (13,20,22), hepatic mRNA levels of FAO controlling genes Acox, Bien, Mcad, and Vlcad (Supplemental Figure 3B) as well as Faldh (Supplemental Figure 3F) were lower in Ppar␣-deficient mice as compared with wild-type mice.…”

“…Total hepatic GST activity was also elevated in wild-type mice upon FO gavage compared with SO, whereas Ppar␣ deficiency further increased GST activity only after SO but not FO (Supplemental Figure 2), indicating that a limit has been achieved in Ppar␣-deficient mice to further increase of the antioxidant capacity. Detoxification of aldehydes generated by LPO occurs also through the activity of fatty aldehyde dehydrogenase (Faldh), a PPAR␣ target gene, which oxidizes long-chain aliphatic aldehydes to FA (20). The expression of hepatic Faldh was markedly decreased in both SO-and FO-treated Ppar␣-deficient mice as compared with wild-type mice, further illustrating the impaired LPO-derived aldehyde detoxification potential in the absence of PPAR␣ ( Figure 1F).…”

“…PPAR␣ has been shown to exert hepatoprotective effects in a range of liver pathologies associated with OS and LPO, such as alcohol-induced liver damage, dietary-induced steatohepatitis, and drug-induced liver failure (16 -18). The beneficial activities of PPAR␣ stem from its ability to improve mitochondrial oxidation, neutralize ROS, and induce enzymes involved in the detoxification of aldehydes generated by alcohol metabolism and LPO (19,20). Ppar␣-deficient mice reveal decreased hepatic expression of genes related to FAO and ketogenesis, leading to aggravated steatohepatitis in mice fed a high saturated-fat diet and an inability to maintain ketone body levels during fasting (13,(21)(22)(23).…”

Paternal obesity in a rodent model affects placental gene expression in a sex-specific manner

“…PPARA is a nuclear transcription factor belonging to the steroid hormone receptor superfamily, targeting genes involved in cell proliferation and inflammation responses. PPARA is the transcriptional master regulator of lipid metabolism (Jump 2008) and can function to protect cells against reactive oxygen species (ROS)-induced apoptosis (Ashibe & Motojima 2009. Inhibition of PPARA induces apoptosis and cellular damage, and the reduced Ppara expression observed in male placentas derived from obese fathers may lead to increased cellular damage .…”

Physiologic Roles of Hepatic Lipid Droplets and Involvement of Peroxisome Proliferator-Activated Receptor .ALPHA. in Their Dynamism

“…Furthermore, potentially toxic compounds may bind to PPARa to activate transcription of the genes for its own detoxifying enzymes, as we showed in the case of induction of fatty aldehyde dehydrogenase. 23,24) In addition, the involvement of PPARa in the induction of metabolic enzymes can be indirect, so that PPARa may be involved in the activation step of other transcription factors or nuclear receptors 18) or in the complex network among the xenobiotic nuclear receptors as suggested in several studies. [25][26][27][28][29][30] Thus not only PPARa but also other nuclear receptors/transcription factors will participate in these processes.…”