title: Diet high in fructose promotes liver steatosis and hepatocyte apoptosis in C57BL/6J female mice: Role of disturbed lipid homeostasis and increased oxidative stress.
abstract: The effects of high (H)-fructose (FR) diet (D) (HFRD) on hepatic lipid homeostasis, oxidative stress, inflammation and hepatocyte apoptosis were investigated in 6-week old female C57BL/6J mice fed a regular chow (ContD) or HFRD (35% fructose-derived calories) for 3 weeks. HFRD-fed mice exhibited increased levels of hepatic steatosis with a significant elevation of serum levels of triglyceride, cholesterol and TNFα compared to ContD-fed mice (P<0.05). HFRD-fed mice exhibited ∼2.7- fold higher levels FAS along with significantly decreased protein levels of adiponection-R2 (∼30%), P-AMPK (∼60%), P-ACC (∼70%) and RXR-α (∼55%), suggesting decreased hepatic fat oxidation compared to controls. Interestingly, hepatic fatty acid uptake into hepatocytes and lipolysis were significantly increased in HFRD-fed mice, as shown by decreased CD36 and fatty acid transporter protein-2, and increased adipose triglyceride lipase, respectively (P<0.05). Increased hepatic levels of iNOS and GSSG/GSH suggest elevated oxidative stress with a higher number of macrophages in the adipose tissue in HFRD-fed mice (P<0.05). Significantly elevated rates of hepatocyte apoptosis (∼2.4-fold), as determined by TUNEL analysis with increased Bax/Bcl2 ratio and PARP-1 levels (∼2- and 1.5-fold, respectively), were observed in HFRD-fed mice. Thus, HFRD exposure increased hepatic steatosis accompanied by oxidative stress and inflammation, leading to hepatocyte apoptosis.
authors.affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Youngshim
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Abdelmegeed
authors.affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA. Electronic address: bj.song@nih.gov.
authors.forename: Byoung-Joon
authors.initials: BJ
authors.lastname: Song
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D005260:Female; D005632:Fructose / Q000009:adverse effects*; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D015434:Panniculitis / Q000139:chemically induced / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: C491899:Fas protein, mouse; D014280:Triglycerides; D019014:fas Receptor; D005632:Fructose; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D005978:Glutathione