Research Article Details
| Article ID: | A16661 |
| PMID: | 28257781 |
| Source: | Food Chem Toxicol |
| 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. |
| DOI: | 10.1016/j.fct.2017.02.039 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | Details |
| S13 | Anti-apoptosis | hepatocyte apoptosis; hepatic autophagy; apoptosis | Pan-caspase inhibitor | Emricasan | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T01 | 5'-AMP-activated protein kinase subunit beta-1 | PRKAB1 | activator | Kinase | Q9Y478 | AAKB1_HUMAN | Details |
| T08 | Tumor necrosis factor | TNF | inhibitor | Cytokine | P01375 | TNFA_HUMAN | Details |
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T20 | Fatty acid synthase | FASN | inhibitor | Enzyme | P49327 | FAS_HUMAN | Details |
| T22 | Stearoyl-CoA desaturase | SCD | inhibitor | Enzyme | O00767 | SCD_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class |
|---|
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D010 | Amoxicillin | Chemical drug | DB01060 | -- | -- | Under clinical trials | Details |
| D158 | Glutathione | Chemical drug | DB00143 | MGST3; HPGDS; GSTM2; GSTM5; GPX7 cofactor; MGST2; GSS; GSTM1; GSTK1; GSTM3; GSTM4; GPX1 cofactor; GPX2 cofactor; GPX3 cofactor | -- | Under clinical trials | Details |
| D142 | Fructose | Chemical drug | DB04173 | -- | Intravenous nutrition drug | Under clinical trials | Details |