Abstract
The liver plays a key role in systemic metabolic processes, which include detoxification, synthesis, storage, and export of carbohydrates, lipids, and proteins. The raising trends of obesity and metabolic disorders worldwide is often associated with the nonalcoholic fatty liver disease (NAFLD), which has become the most frequent type of chronic liver disorder with risk of progression to cirrhosis and hepatocellular carcinoma. Liver mitochondria play a key role in degrading the pathways of carbohydrates, proteins, lipids, and xenobiotics, and to provide energy for the body cells. The morphological and functional integrity of mitochondria guarantee the proper functioning of β-oxidation of free fatty acids and of the tricarboxylic acid cycle. Evaluation of the liver in clinical medicine needs to be accurate in NAFLD patients and includes history, physical exam, imaging, and laboratory assays. Evaluation of mitochondrial function in chronic liver disease and NAFLD is now possible by novel diagnostic tools. “Dynamic” liver function tests include the breath test (BT) based on the use of substrates marked with the non-radioactive, naturally occurring stable isotope 13C. Hepatocellular metabolization of the substrate will generate 13CO2, which is excreted in breath and measured by mass spectrometry or infrared spectroscopy. Breath levels of 13CO2 are biomarkers of specific metabolic processes occurring in the hepatocyte cytosol, microsomes, and mitochondria. 13C-BTs explore distinct chronic liver diseases including simple liver steatosis, non-alcoholic steatohepatitis, liver fibrosis, cirrhosis, hepatocellular carcinoma, drug, and alcohol effects. In NAFLD, 13C-BT use substrates such as α-ketoisocaproic acid, methionine, and octanoic acid to assess mitochondrial oxidation capacity which can be impaired at an early stage of disease. 13C-BTs represent an indirect, cost-effective, and easy method to evaluate dynamic liver function. Further applications are expected in clinical medicine. In this review, we discuss the involvement of liver mitochondria in the progression of NAFLD, together with the role of 13C-BT in assessing mitochondrial function and its potential use in the prevention and management of NAFLD.
Highlights
The liver plays a key role in lipid homeostasis, with steps including the synthesis, oxidation, and transport of free fatty acids (FFA), triglycerides (TG), cholesterol, and bile acids (BA)
We found that ketoisocaproic acid (KICA) decarboxylation was defective in patients with histologically-proven advanced nonalcoholic steatohepatitis (NASH) but not in patients with simple steatosis [147] (Figure 6)
We found that KICA decarboxylation was decreased in cirrhotic patients with hepatocellular carcinoma (HCC) compared with cirrhotic patients without HCC and identical Child— Pugh scores [158], i.e., a classification ranging from score 5 to 15 which incorporates five variables for assessing the prognosis of liver cirrhosis [186]
Summary
The liver plays a key role in lipid homeostasis, with steps including the synthesis, oxidation, and transport of free fatty acids (FFA), triglycerides (TG), cholesterol, and bile acids (BA). The hepatocyte can be damaged by various hits and intracellular organelles can be part of the dysfunctional cell, with changes including microsomal hypertrophy, mitochondrial damage by free fatty acids overload and insufficient β-oxidation and activation of peroxisomal metabolism. Growing evidence points to dysfunctional mitochondria as key contributors in the pathogenesis of the chronic metabolic conditions (i.e., obesity, metabolic syndrome and type 2 diabetes mellitus) frequently linked to liver disease. These processes act through pathways leading to oxidative stress, chronic inflammation, and insulin resistance. Mitochondria play a key role in the metabolic pathways and signalling networks [6]. Essential elements include mitochondrial DNA (mtDNA), membrane constituents, lipoprotein trafficking, pro- and anti-oxidant balance, and metabolic demand and supply [10]
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