Mitochondria Matter: Systemic Aspects of Nonalcoholic Fatty Liver Disease (NAFLD) and Diagnostic Assessment of Liver Function by Stable Isotope Dynamic Breath Tests

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.

The role of microbiota in nonalcoholic fatty liver disease

“…Phenotypically, a set of metabolic abnormalities play a major role in the onset and progression of NAFLD, contributing to the obesogenic, lipotoxic scenario which results in increased insulin resistance. The hepatic consequence is excessive accumulation of (long‐chain) free fatty acids, oxidative stress, lipid peroxidation and mitochondrial dysfunction 4,59,60 . In this respect, the reader should also refer to recent publications from our group 1,4 …”

Oxidative Stress in Non-Alcoholic Fatty Liver Disease

“…This promotes NADH production by tricarboxylic acid cycle enzymes and increases ATP synthesis and ROS production. In addition, increased levels of calcium in the mitochondrial matrix induce further mitochondrial permeability transition pore (mPTP) opening, promoting apoptotic processes in the long term [154,170].…”

“…The importance of assessing mitochondrial function in chronic liver diseases, such as NAFLD and its evolved forms, is, therefore, evident, thanks also to new diagnostic tools. One test recently introduced, although still in the process of implementation, is the 13C breath test (BT) [170]. This is a "dynamic" liver function test based on the use of substrates labeled with the sTable 13 C isotope, which is a natural, non-radioactive element.…”

The Involvement of Human Papilloma Virus in Gastrointestinal Cancers

“…Chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), aflatoxin-contaminated foods, and heavy alcohol intake are the main risk factors for HCC. Further, excess body weight along with type 2 diabetes as components of the metabolic syndrome act as predisposing factors to the metabolic-associated fatty liver disease (non-alcoholic fatty liver disease) and progression to liver fibrosis, cirrhosis, and HCC [ 141 , 142 , 143 , 144 , 145 , 146 ].…”