Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver

Assessment of Hepatic Mitochondrial Oxidation and Pyruvate Cycling in NAFLD by 13C Magnetic Resonance Spectroscopy

“…Such high rates of hepatic pyruvate cycling would use a significant fraction of the ATP available, and place the hepatocyte in a metabolically precarious position. In a recent study we found that an intra-arterial infusion of propionate, that was lower than (Hasenour et al, 2015; Jin et al, 2005; Jin et al, 2004; Satapati et al, 2015) or similar to (Sunny et al, 2011) the total amount of sodium propionate administered in previous studies, dose-dependently increased: hepatic propionyl CoA concentrations up to 18 fold, hepatic pyruvate cycling up to 20–30 fold, hepatic TCA intermediates (malate and succinate) and aspartate by 2–3 fold, and rates of hepatic glucose production by up to 2 fold in awake rats (Perry et al, 2016). It is well established that propionyl CoA potently stimulates pyruvate carboxylase activity and flux (Perry et al, 2016; Scrutton, 1974) and this may explain at least in part the large increases in hepatic pyruvate carboxylase flux and pyruvate cycling that Sunny et al observed in their [1,2,3- 13 C 3 ]propionate labeling studies of hepatic mitochondrial metabolism in humans (Sunny et al, 2011).…”

“…Under fasting conditions, when hepatic gluconeogenesis is the major contributor to whole body glucose production, the liver would therefore be expected to limit futile cycling through pyruvate kinase. In this regard it was surprising that several studies using [1,2,3- 13 C 3 ]propionate as a metabolic tracer have reported extremely high rates of hepatic pyruvate cycling, which were 3–4 times the rate of hepatic mitochondrial oxidation flux and 4–6 times the rates of gluconeogenesis in both rodents (Jin et al, 2004; Satapati et al, 2015) and humans (Sunny et al, 2011). Such high rates of hepatic pyruvate cycling would use a significant fraction of the ATP available, and place the hepatocyte in a metabolically precarious position.…”

“…As such, periportal hepatocytes take up and metabolize much more propionate than perivenous hepatocytes, which invalidates many of the assumptions required for the metabolic flux rate calculations using this method. The effects of zonation on [1,2,3- 13 C 3 ]propionate metabolism alone could explain a large proportion of the wide variation in flux estimates from livers perfused with 0.1 vs. 0.5 mM of [1,2,3- 13 C 3 ]propionate where the higher concentrations of propionate increased hepatic phosphoenolpyruvate carboxykinase flux and pyruvate carboxylase kinase flux 2 to 4 fold (Burgess et al, 2007; Satapati et al, 2015). Furthermore the impact of zonation on estimates of hepatic metabolic fluxes will be even greater with lower doses of [1,2,3- 13 C 3 ]propionate when a greater proportion of [1,2,3- 13 C 3 ]propionate will be metabolized by the periportal heptatocytes.…”

“…Concerns have also been raised regarding the use of acetate and lactate as tracers of hepatic metabolism (Burgess et al, 2015; Previs and Kelley, 2015; Satapati et al, 2015). In regards to acetate, it is possible that extra-hepatic or hepatic metabolism of 13 C labeled acetate can lead to significant 13 C labeling of glutamine and 13 CO 2 , which in turn could potentially impact the 13 C labeling in hepatic glutamate.…”

Treating fatty liver disease by modulating mitochondrial pyruvate metabolism

“…At its core, NAFLD is caused by fat accumulation that is likely driven by nutrient excess. At the same time, the progression to NASH in mice and humans has been tightly linked to a number of factors, including insulin resistance,14, 15 abnormal mitochondrial function,16, 17, 18, 19 oxidative damage, and hepatic inflammation, that promote a state conducive to necropoptosis and replacement of dead hepatocytes with a collagen matrix secreted by hepatic stellate cells in response to these stimuli 20, 21. It is interesting to note that the entire spectrum of this pathophysiology from insulin resistance to fibrotic scarring may involve dysfunctional metabolism driven by overnutrition.…”