Overexpression of Nudt7 decreases bile acid levels and peroxisomal fatty acid oxidation in the liver

Abstract

Lipid metabolism requires CoA, an essential cofactor found in multiple subcellular compartments, including the peroxisomes. In the liver, CoA levels are dynamically adjusted between the fed and fasted states. Elevated CoA levels in the fasted state are driven by increased synthesis; however, this also correlates with decreased expression of Nudix hydrolase (Nudt)7, the major CoA-degrading enzyme in the liver. Nudt7 resides in the peroxisomes, and we overexpressed this enzyme in mouse livers to determine its effect on the size and composition of the hepatic CoA pool in the fed and fasted states. Nudt7 overexpression did not change total CoA levels, but decreased the concentration of short-chain acyl-CoAs and choloyl-CoA in fasted livers, when endogenous Nudt7 activity was lowest. The effect on these acyl-CoAs correlated with a significant decrease in the hepatic bile acid content and in the rate of peroxisomal fatty acid oxidation, as estimated by targeted and untargeted metabolomics, combined with the measurement of fatty acid oxidation in intact hepatocytes. Identification of the CoA species and metabolic pathways affected by the overexpression on Nudt7 in vivo supports the conclusion that the nutritionally driven modulation of Nudt7 activity could contribute to the regulation of the peroxisomal CoA pool and peroxisomal lipid metabolism.

The Overlooked Transformation Mechanisms of VLCFAs: Peroxisomal β-Oxidation

“…And a recent study found that sirtuin 5 (SIRT5) functions similarly to mTOR, which shuts down peroxisomal β-oxidation by inhibiting the activity of ACOX1 [114]. Other reports have studied CoA in the process of β-oxidation and found that Nudt7 and Nudt19 in the Nudt superfamily can exert positive effects on CoA substrates in certain metabolic processes to promote the metabolic process [115,116]. With the upsurge of research on noncoding RNAs (ncRNAs), some play positive or inhibitory roles in peroxisomal β-oxidation, such as miR-222, miR-25-3p, circ_0005379, and others [117][118][119][120][121][122], which mainly target the rate-limiting enzyme ACOX1.…”

Nudt8 is a novel CoA diphosphohydrolase that resides in the mitochondria

“…At the whole tissue level, the concentration of CoA changes with the metabolic state by coordinating synthesis and degradation. In the liver, activation of the biosynthetic pathway drives the increase in CoA that occurs in the transition between the fed and fasted state [11,12]. Conversely, the net decrease in the concentration of hepatic CoA observed upon refeeding after a fast requires both inhibition of de novo CoA synthesis and degradation of the cofactor accumulated in the fasted state.…”

“…In the peroxisomes of liver and kidneys, CoA is hydrolyzed to 3 0 ,5 0 -ADP and (acyl-)phosphopantetheine by two Nudix hydrolases, Nudt7 and Nudt19, respectively [13][14][15][16]. Unlike intact CoA, these smaller degradation products can exit the peroxisomes [17]; thus, the activity of Nudt7 and Nudt19 likely plays an important role in the regulation of the peroxisomal CoA pool and, in turn, CoA-dependent peroxisomal metabolism [12,17,18]. Consistent with such a role, the expression of Nudt7 and the activity of Nudt19 are higher in the fed state compared to the fasted state Abbreviations GAPDH, glyceraldehyde-3-phosphate dehydrogenase; mBB, monobromobimane; PMP70, ATP-binding cassette, subfamily D, member 3. and inversely correlate with tissue CoA levels in the liver and kidneys, respectively [13,16,19].…”

“…In the liver, activation of the biosynthetic pathway drives the increase in CoA that occurs in the transition between the fed and fasted state [11,12]. In the liver, activation of the biosynthetic pathway drives the increase in CoA that occurs in the transition between the fed and fasted state [11,12].…”

Peroxisomal Metabolite and Cofactor Transport in Humans

“…How these degradation products are exported out of peroxisomes is not clear. The importance of NUDT7 in peroxisomal metabolism was shown in metabolomics analysis of mice that overexpress NUDT7 in the liver, which revealed a decrease in peroxisomal beta-oxidation and bile acid biosynthesis rates ( Shumar et al, 2019 ). Nudt19-/- mice showed a 20% increase in CoA in the kidney ( Shumar et al, 2018 ; Figure 1A ).…”