Abstract
Aim: We compared the efficacy of n3-polyunsaturated fatty acids (n3-PUFAs) and metformin in halting the progression of non-alcoholic fatty liver disease (NAFLD) developed in the milieu of insulin deficiency. Main methods: NAFLD was induced by a chronic high-fat diet (HFD) in male Sprague Dawley rats, rendered diabetic by a low dose streptozotocin (STZ). Diabetic rats were treated with n3-PUFAs (300 mg/kg/d) or metformin (150 mg/kg/d) for 8 weeks. Improvements in the NAFLD score and hepatic insulin resistance (IR) were addressed and correlated to changes in the hepatic expression of Forkhead box protein O1 (FOXO-1), microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B) and gamma-aminobutyric acid receptor-associated protein-like 1 (GABARAPL1) genes. Hepatic peroxisome proliferator-activated receptor alpha (PPAR-α), and B-cell lymphoma 2 (Bcl-2) protein expression was also assessed. Key findings: Driven by insulin deficiency and HFD, the FOXO-1 gene along with its downstream targets, MAP1LC3B and GABARAPL1, were highly expressed in the liver tissue of the HFD/STZ group. Meanwhile, hepatic expression of PPAR-α and Bcl-2 was markedly decreased. These abnormalities coincided with a marked increase in the hepatic IR and NAFLD activity. Comparable to metformin, n3-PUFAs were able to rearrange hepatic PPAR-α and FOXO-1 expression in HFD/STZ rats, resulting in improved diabetic/steatotic liver phenotype. Significance: Along with the enhancement of PPAR-α expression, inhibition of FoxO1/GABARAPL1/MAP1LC3B transcription is suggested as a core mechanism for the protective effects of n3-PUFAs on hepatic IR and NAFLD. Under conditions of insulin deficiency, n3-PUFAs retain their potential as a safe and promising approach for the control of NAFLD.
Original language | English (US) |
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Article number | 121145 |
Journal | Life sciences |
Volume | 311 |
DOIs | |
State | Published - Dec 15 2022 |
Externally published | Yes |
Keywords
- FOXO-1
- GABARAPL1
- HFD/STZ
- NAFLD
- PPAR-α
- n3-polyunsaturated fatty acids
ASJC Scopus subject areas
- General Pharmacology, Toxicology and Pharmaceutics
- General Biochemistry, Genetics and Molecular Biology