Occludin regulates glucose uptake and ATP production in pericytes by influencing AMP-activated protein kinase activity

Abstract

Energetic regulation at the blood-brain barrier is critical for maintaining its integrity, transport capabilities, and brain demands for glucose. However, the underlying mechanisms that regulate these processes are still poorly explored. We recently characterized the protein occludin as a NADH oxidase and demonstrated its influence on the expression and activation of the histone deacetylase SIRT-1. Because SIRT-1 works in concert with AMP-activated protein kinase (AMPK) (AMPK), we investigated the impact of occludin on this metabolic switch. Here we show that in blood-brain barrier pericytes, occludin promotes AMPK expression and activation, influencing the expression of glucose transporters GLUT-1 and GLUT-4, glucose uptake, and ATP content. Furthermore, occludin expression, AMP-dependent protein kinase activity, and glucose uptake were altered under inflammatory (TNFα) and infectious (HIV) conditions. We also show that pericytes share glucose and mitochondria with astrocytes, and that occludin levels modify the ability of pericytes to share those energetic resources. In addition, we demonstrate that murine mitochondria can be transferred from live brain microvessels to energetically impaired human astrocytes, promoting their survival. Our findings demonstrate that occludin plays an important role in blood-brain barrier pericyte metabolism by influencing AMPK protein kinase activity, glucose uptake, ATP production, and by regulating the ability of pericytes to interact metabolically with astrocytes.

Occludin, caveolin‐1, and Alix form a multi‐protein complex and regulate HIV‐1 infection of brain pericytes

“…52 Modification of the cav-1-ocln-Alix complex by overexpression of ocln also resulted in a prominent decrease in p24 levels in HIV-1-infected pericyte cultures ( Figure 6). These findings are consistent with our reports 25 in which we characterized ocln as a novel NADH oxidase that inhibits HIV-1 transcription by controlling SIRT-1 expression and activation in human brain pericytes. The inverse relationship between ocln and HIV-1 transcription was further substantiated when it was shown that occludin silencing resulted in 75% and 250% increase in viral transcription in human primary macrophages and differentiated monocytic U937 cells, respectively.…”

“…[20][21][22] Occludin (ocln) is a transmembrane TJ protein 24 ; however, recent evidence has shown an important role of this protein in regulating cellular metabolism through influencing AMPK protein kinase activity, ATP production, and glucose uptake. 25 Importantly, ocln can control the responses of human pericytes to HIV-1 and influence the level of infection. 20 Another membrane protein that is involved both in maintaining BBB integrity and HIV-1 infection is caveolin-1 (cav-1).…”

The energetic brain – A review from students to students

“…Furthermore, astrocytes and pericytes express comparable amounts of GLUT1 and GLUT4 (Castro et al . ).…”

Metabolic Coordination of Pericyte Phenotypes: Therapeutic Implications

“…for both GLUT1 and GLUT4 are detectable in human and murine brain pericytes (Castro et al, 2018;He et al, 2018;Vanlandewijck et al, 2018), indicating that glucose uptake can occur via both insulin-dependent and independent pathways. This may explain the greater maximum glucose transport capacity observed in bovine retinal pericytes as compared to endothelial cells (which uptake glucose exclusively through GLUT1) (Mandarino et al, 1994).…”