Sheldon 2015 Abstract MiPschool Greenville 2015

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eNOS is required to preserve hepatic mitochondrial function in western diet-induced nonalcoholic fatty liver disease.

Link:

Sheldon RD, Linden MA, Morris EM, Meers GM, Laughlin MH, Rector RS (2015)

Event: MiPschool Greenville 2015

Endothelial nitric oxide synthase (eNOS) produces physiological concentrations of nitric oxide that can influence mitochondrial biogenesis and electron transport chain activity. Hepatic mitochondrial dysfunction is a hallmark feature of nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms of this phenomenon remain elusive. Here, we tested the hypothesis that eNOS is required for proper hepatic mitochondrial function in NAFLD. Wild-type (WT) and eNOS knockout (eNOS-/-) mice received either control (CON; 10% fat, 3.5% sucrose) or a western diet high in fat (45%), sucrose (17%) and cholesterol (1%; HFC) for 18-weeks. HFC diet feeding induced histological NAFLD and increased weight gain and % body fat in both genotypes compared to CON diet. Complete hepatic mitochondrial palmitate oxidation to CO2 was elevated in both eNOS-/- groups compared with WT mice (p<0.05), while incomplete acid-soluble metabolite production was elevated only in eNOS-/--CON compared to other groups. In addition, maximal FCCP-uncoupled mitochondrial respiration tended to be elevated in eNOS-/--CON compared to WT-CON (+24%; p=0.08) but was significantly reduced with HFC feeding in eNOS-/- mice (-37% vs eNOS-/--CON; p<0.05). Finally, HFC feeding dramatically reduced hepatic mRNA expression of the putative control marker for mitochondrial biogenesis, PGC-1α, in WT (-30%) and eNOS-/- (-60%) compared with WT-CON (p<0.05). These data suggest that eNOS-/- mice are more susceptible to Western diet-induced hepatic mitochondrial dysfunction that may be related to an impaired capacity to generate new, healthy mitochondria.


O2k-Network Lab: US MO Columbia Rector RS


Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Exercise physiology;nutrition;life style 


Organism: Mouse  Tissue;cell: Liver 


Coupling state: LEAK, OXPHOS, ET  Pathway: N, NS  HRR: Oxygraph-2k  Event: Oral 


Affiliations

Harry S Truman Memorial Veterans Med Center and Univ Missouri, Columbia, MO, USA - rdsheldon@mail.missouri.edu

Figures

MiPschool2015Greenville Sheldon Figure1.jpg
Figure 1. Functional measures of isolated hepatic mitochondria. *; Main effect of diet. #; Main effect of genotype. %; significant interaction, eNOS-/--HFC different from WT-HFC. $; significant interaction, eNOS-/--CON different from eNOS-/--HFC.


MiPschool2015Greenville Sheldon Figure2.jpg
Figure 2. Markers of mitochondrial biogenesis in whole liver homogenate. *; Main effect of diet. #; Main effect of genotype. %; significant interaction, eNOS-/--HFC different from WT-HFC. $; significant interaction, eNOS-/--CON different from eNOS-/--HFC.





Support

Supported by: HL036088 (MHL) and VHA-CDA2 1299-03(RSR)