Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and represents the hepatic expression of several metabolic abnormalities of high epidemiologic relevance. Fat accumulation in the hepatocytes results in cellular fragility and risk of progression toward necroinflammation, i.e., nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Several pathways contribute to fat accumulation and damage in the liver and can also involve the mitochondria, whose functional integrity is essential to maintain liver bioenergetics. In NAFLD/NASH, both structural and functional mitochondrial abnormalities occur and can involve mitochondrial electron transport chain, decreased mitochondrial β-oxidation of free fatty acids, excessive generation of reactive oxygen species, and lipid peroxidation. NASH is a major target of therapy, but there is no established single or combined treatment so far. Notably, translational and clinical studies point to mitochondria as future therapeutic targets in NAFLD since the prevention of mitochondrial damage could improve liver bioenergetics.
Highlights
The liver plays a key role in lipid homeostasis, which includes synthesis, oxidation, and transport of free fatty acids (FFA), triglycerides (TG), cholesterol, and bile acids (BA).Excess accumulation of fat in the liver encompasses several conditions involved in the onset and progression of hepatic steatosis
The term nonalcoholic fatty liver disease (NAFLD) refers to hepatic steatosis due to unknown causes, encompassing a spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cryptogenic cirrhosis, and hepatocellular carcinoma (HCC)
Additional factors contributing to NAFLD include the environment, gut microbiome, deranged glucose-lipid metabolic pathways, metabolic inflammation primarily mediated by innate immune signaling, adipocytokine impairment (e.g., tumor necrosis factor (TNF)-α, adiponectin, resistin, leptin, angiotensin II), and comorbidities [2,3,4]
Summary
The liver plays a key role in lipid homeostasis, which includes synthesis, oxidation, and transport of free fatty acids (FFA), triglycerides (TG), cholesterol, and bile acids (BA). Several studies show that deranged mitochondrial function can contribute to fat accumulation and damage in the liver by increased production of reactive oxygen species (ROS), oxidative stress, and defective bioenergetics. These steps likely contribute to the progression of liver disease from NAFL to NASH by mechanisms involving hepatic inflammation, necrosis, and fibrosis. [17]can can enter made fromlipolysis lipolysisofoftriglycerides triglycerides (TG) in enter thethe hepatocyte hepatocyte by using specific transporters, translocase/CD36 transporter, fatty acid-binding protein by using specific transporters, These are as- in the (2) dietary FFA (about 15%) contained in TG within ApoE-enriched chylomicrons. FABP, fatty acid-binding protein; FFA, free fatty acids; TG, triglycerides VLDL, very-low-density lipoproteins
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