Induction of BVR-A Expression by Korean Red Ginseng in Murine Hippocampal Astrocytes: Role of Bilirubin in Mitochondrial Function via the LKB1–SIRT1–ERRα Axis

Abstract

The beneficial effects of Korean red ginseng extract (KRGE) on the central nervous system (CNS) have been reported. Among the CNS cells, astrocytes possess robust antioxidative properties and regenerative potential. Under physiological conditions, biliverdin reductase A (BVR-A) converts biliverdin (a heme oxygenase metabolite) into bilirubin, a major natural and potent antioxidant. We found that KRGE enhanced BVR-A in astrocytes in the fimbria region of the adult mouse hippocampus under physiological conditions. KRGE-induced BVR-A expression and subsequent bilirubin production were required for changes in mitochondrial membrane potential, mitochondrial mass, and oxidative phosphorylation through liver kinase B1 (LKB1), estrogen-related receptor α (ERRα), and sirtuin (SIRT1 and SIRT5) in astrocytes. However, BVR-A did not affect the KRGE-induced expression of AMP-activated protein kinase α (AMPKα). The KRGE-stimulated BVR-A–LKB1–SIRT1–ERRα pathway regulates the levels of mitochondria-localized proteins such as SIRT5, translocase of the outer mitochondrial membrane 20 (Tom20), Tom22, cytochrome c (Cyt c), and superoxide dismutase 2 (SOD2). Increased Tom20 expression in astrocytes of the hippocampal fimbria region was observed in KRGE-treated mice. KRGE-induced expression of Cyt c and SOD2 was associated with the Tom20/Tom22 complex. Taken together, KRGE-induced bilirubin production is required for enhanced astrocytic mitochondrial function in an LKB1-dependent and AMPKα-independent manner under physiological conditions.

The effects of Korean Red Ginseng on heme oxygenase-1 with a focus on mitochondrial function in pathophysiologic conditions

“…Under oxidative stress, biliverdin reductase A (BVR-A) acts as a transcription factor for HO-1 [ 22 ]. However, we could not determine the BVR-A–HO–1 axis in astrocytes under physiological conditions [ 23 ]. Collectively, Keap1 and BVR-A may have different susceptibilities to oxidative stress in KRG-treated physiological environments.…”

“…KRG-induced HIF-1α increases the expression of mitochondrial functional proteins involved in processes including oxidative phosphorylation (OXPHOS) and ATP production [ 13 ]. KRG increases HIF-1α protein expression under normoxic conditions, partly due to increased KRG-mediated enhancement of mitochondrial mass and O 2 consumption [ 13 , 23 ].…”

“…KRG-administered murine brain tissues show increased levels of BVR-A in hippocampal astrocytes [ 23 ]. Conversion of biliverdin to bilirubin by BVR-A upregulates SOD2, leading to the blocking of excessive reactive oxygen species production [ 23 ].…”

“…KRG-administered murine brain tissues show increased levels of BVR-A in hippocampal astrocytes [ 23 ]. Conversion of biliverdin to bilirubin by BVR-A upregulates SOD2, leading to the blocking of excessive reactive oxygen species production [ 23 ]. In addition, the KRG-mediated BVR-A/bilirubin pathway upregulates estrogen-related receptor α (ERRα) [ 23 ], which is an important transcription factor for VEGF, by binding to peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) [ 27 ].…”

“…Conversion of biliverdin to bilirubin by BVR-A upregulates SOD2, leading to the blocking of excessive reactive oxygen species production [ 23 ]. In addition, the KRG-mediated BVR-A/bilirubin pathway upregulates estrogen-related receptor α (ERRα) [ 23 ], which is an important transcription factor for VEGF, by binding to peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) [ 27 ]. ERRα pathway is considered as a critical regulator of mitochondrial biogenesis-related functions [ 26 , 28 ].…”