Influence of hypoxia on mitochondrial function and energy status in CCl4-induced cirrhotic rat liver

Abstract

The influence of hypoxia on hepatic mitochondrial function and energy status was studied in normal and carbon tetrachloride (CCl4)-induced cirrhotic rats. Under hypoxemia of 50 mm Hg-PaO2, hepatic energy status was suppressed both in normal and cirrhotic rats. After the reversal of hypoxia, it was completely restored in normal rats concomitant with a rapid elevation of hepatic mitochondrial redox state (overshoot phenomenon) and increase in the mitochondrial oxidative phosphorylative activity. By contrast, in cirrhotic rats, such an enhancement of mitochondrial function was not observed. It was clarified that cirrhotic liver mitochondrial function was not observed. It was clarified that cirrhotic liver mitochondria have little capacity to respond to the hypoxic stress. A lower resistance to hypoxic episode in cirrhotics might be attributable to the absence of mitochondrial enhancement which is a compensatory mechanism for the deranged energy metabolism of the liver.

31P and1H NMR spectroscopic studies of liver extracts of carbon tetrachloride-treated rats

“…Rather, these studies showed that cirrhosis disturbs cell redox states, as measured from increased cytoplasmic lactate:pyruvate ratios 30 and decreased acetoacetate/b-hydroxybutyrate ratios. 28,30 We also found other metabolic changes in cirrhosis that may not be directly related to hypoxia. There was a significant decrease of 40% observed in the NAD levels of cirrhotic rats, when expressed as a percentage of total phosphorus content.…”

“…These results are supported by previous reports that CCl 4 -induced cirrhotic rats showed decreases in hepatic ATP, ATP:ADP ratio and energy charge levels. 28,29 Experimental hypoxia in perfused rat livers resulted in decreased ATP levels, increased ADP and P i levels, and a 50% reduction in ATP:ADP ratios. 6,17 NMR studies in humans have also shown diminished ATP and an increased P i :ATP ratio in the cirrhotic liver.…”

The Effect of Oxygen Supplementation on the Arterial Ketone Body Ratio in Human Cirrhosis

“…In rat models of cirrhosis, hepatic mitochondrial function has been shown to be impaired as evidenced by reduced hepatic energy charge [1, 2, 3]and decreased rates of ATP production [4]. Hepatic mitochondrial function has also been indirectly assessed in humans by measuring the arterial ketone body ratio (AKBR) which reflects mitochondrial NAD + /NADH ratio and energy state.…”