Abstract
BackgroundFat accumulation in the liver contributes to the development of non-alcoholic fatty liver disease (NAFLD). N-acetylcysteine (NAC) is an antioxidant, acting both directly and indirectly via upregulation of cellular antioxidants. We examined the mechanisms of liver steatosis after 12 months high fat (HF) diet and tested the ability of NAC to rescue liver steatosis.MethodsSeven-week-old C57BL/6 (B6) male mice were administered HF diet for 12 months (HF group). Two other groups received HF diet for 12 months accompanied by NAC for 12 months (HFD + NAC(1–12)) or 6 months (HFD + NAC(1–6)). The control group was fed regular diet for 12 months (CD group).ResultsLiver steatosis was more pronounced in the HF group than in the CD group after 12 month feeding. NAC intake for 6 or 12 months decreased liver steatosis in comparison with HF diet (p < 0.05). Furthermore, NAC treatment also reduced cellular apoptosis and caspase-3 expression. In the unfolded protein response (UPR) pathway, the expression of ECHS1, HSP60, and HSP70 was decreased in the HFD group (p < 0.05) and rescued by NAC therapy. With regards to the endoplasmic reticulum (ER) stress, Phospho-PERK (p-PERK) and ATF4 expression was decreased in the HF group, and only the HFD + NAC(1–12), but not HFD + NAC(1–6) group, showed significant improvement.ConclusionHF diet for 12 months induces significant liver steatosis via altered ER stress and UPR pathway activity, as well as liver apoptosis. NAC treatment rescues the liver steatosis and apoptosis induced by HF diet.
Highlights
Fat accumulation in the liver contributes to the development of non-alcoholic fatty liver disease (NAFLD)
Mice were divided into five groups: (1) chow diet group [(CD), 3.85 kcal/g dry wt, 19.2 g/100 g protein, 67.3 g/100 g carbohydrate, and 4.3 g/100 g saturated fat]; (2) chow diet with 10 mMNAC (Sigma-Aldrich/A9165, Louis, MO, USA) dissolved in water administered for 12 months (CD + NAC); (3) high-fat diet group[(HF), 5.56 kcal/g dry wt, 23 g/100 g protein, 35.5 g/100 g carbohydrate, and 35.8 g/100 g saturated fat mostly in the form of lard (58 kcal% fat, Research Diets/D12331, New Brunswick, NJ, USA)] after weaning; (4) high fat (HF) with 10 mM NAC after weaning for 12 months (HF + NAC(1–12)); (5) HF supplemented with 10 mM NAC for the first 6 months of treatment after weaning (HF + NAC(1–6))
Liver weight and triglyceride The body weight increased in the HF group, and NAC treatment significantly reversed this effect (Fig. 1a)
Summary
Fat accumulation in the liver contributes to the development of non-alcoholic fatty liver disease (NAFLD). The “multiple hit pathogenesis” hypothesis, proposed to explain the origin of NAFLD, is multifactorial, including genetic, epigenetic, metabolic, and environmental parameters. These factors lead to the accumulation of fat, Tsai et al Lipids in Health and Disease (2020) 19:105 like triglycerides, in hepatocytes, rendering them more susceptible to certain stress types, such as oxidative stress, ATP depletion, and endotoxins. These cause inflammation, cellular death, and fibrosis [5]. Mitochondrial dysfunction results in reactive oxygen species (ROS) overproduction, causing abnormal respiration, and stimulates NAFLD development [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
