Abstract
Nonalcoholic fatty liver disease (NAFLD) is a dysmetabolic hepatic damage of increasing severity: simple fat accumulation (steatosis), nonalcoholic steatohepatitis (NASH), and hepatic fibrosis. Oxidative stress is considered an important factor in producing hepatocyte injury associated with NAFLD progression. Studies also suggest a link between the accumulation of specific hepatic lipid species, mitochondrial dysfunction, and the progression of NAFLD. However, it is unclear whether mitochondrial lipid modifications are involved in NAFLD progression. To gain insight into the relationship between mitochondrial lipids and disease progression through different stages of NAFLD, we performed lipidomic analyses on mouse livers at different stages of western diet-induced NAFLD, with or without hepatic fibrosis. After organelle separation, we studied separately the mitochondrial and the “nonmitochondrial” hepatic lipidomes. We identified 719 lipid species from 16 lipid families. Remarkably, the western diet triggered time-dependent changes in the mitochondrial lipidome, whereas the “nonmitochondrial” lipidome showed little difference with levels of hepatic steatosis or the presence of fibrosis. In mitochondria, the changes in the lipidome preceded hepatic fibrosis. In particular, two critical phospholipids, phosphatidic acid (PA) and cardiolipin (CL), displayed opposite responses in mitochondria. Decrease in CL and increase in PA were concurrent with an increase of coenzyme Q. Electron paramagnetic resonance spectroscopy superoxide spin trapping and Cu2+ measurement showed the progressive increase in oxidative stress in the liver. Overall, these results suggest mitochondrial lipid modifications could act as an early event in mitochondrial dysfunction and NAFLD progression.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is reaching epidemic proportions, affecting a quarter of the world’s adult population [1]
Mice with western diet (WD) developed obesity, increased liver weight normalized to body weight, hepatic steatosis, ASAT, ALAT, and liver fibrosis
Fibrosis was delayed, appearing at week 25 only as opposed to steatosis that was present from week 8 (Figures 1(a)–1(f)). mRNA expression of the key transcription factor for lipid synthesis, Sterol Regulatory ElementBinding Transcription Factor 1 (Srebf1), was increased, while that of the nuclear receptor peroxisome proliferatoractivated receptor α (Pparα) was decreased
Summary
Nonalcoholic fatty liver disease (NAFLD) is reaching epidemic proportions, affecting a quarter of the world’s adult population [1]. NAFLD begins with an accumulation of cellular fat (steatosis), progresses to hepatocellular injury with inflammation (nonalcoholic steatohepatitis (NASH)), and culminates in hepatic fibrosis, a cause of liver cirrhosis and hepatocellular carcinoma [2]. The current mechanistic view of the progression of simple steatosis into NASH proposes that exceeding the elimination capacity of free fatty acids in hepatocytes contributes to the formation of lipotoxic species, endoplasmic reticulum (ER) stress, and maladaptive responses of mitochondria (mitochondrial dysfunction) [3,4,5]. As the power house of hepatocytes, mitochondria play a major role in oxidative metabolism and normal function of the liver. In the early stages of NAFLD, namely, simple steatosis, mitochondrial respiration increases to adapt to the higher substrate availability and increased ATP demand.
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