Research Article Details

Article ID: A07987
PMID: 32289432
Source: Life Sci
Title: High-altitude chronic hypoxia ameliorates obesity-induced non-alcoholic fatty liver disease in mice by regulating mitochondrial and AMPK signaling.
Abstract: AIMS: High-fat intake induces obesity and non-alcoholic fatty liver disease (NAFLD). However, high-altitude chronic hypoxia might alleviate NAFLD progression through improved mitochondrial function and AMP-activated protein kinase (AMPK) signaling. We hypothesized that high-altitude chronic hypoxia would have protective effects against NAFLD development. MAIN METHODS: C57BL/6J mice were randomly divided into control (normal diet and altitude 50&#160;m), CHH (normal diet and altitude 4300&#160;m), HFD (high-fat diet and altitude 50&#160;m), and HFD-CHH (high-fat diet and altitude 4300&#160;m) groups. After being maintained for 8&#160;weeks under the appropriate conditions, mice were evaluated. KEY FINDINGS: The degree of liver lipid accumulation and expression of the lipid synthesis-related genes acetyl-CoA carboxylase1 (ACC1), fatty acid synthesis (FAS), and sterol regulatory element binding protein-1c (SREBP-1c) were reduced in the HFD-CHH group; however, expression of the lipolysis-related gene carnitine palmitoyl transferase 1 (CPT1) was increased. Furthermore, in addition to increased expression of mitochondrial biogenesis-related genes, mitochondrial respiratory function and mitochondrial DNA content were elevated in the HFD-CHH group compared to those in the HFD group. The HFD-CHH group also exhibited significantly increased antioxidation activity and decreased reactive oxygen species production (P&#160;<&#160;0.05). Finally, AMPK signaling in the liver was activated and the expression of phosphorylated-AMPK (P-AMPK) was significantly increased in the HFD-CHH group. SIGNIFICANCE: Collectively, our findings suggest that high altitude-induced hypoxia might improve impaired mitochondrial function and activate AMPK signaling in obesity-induced NAFLD. High-altitude chronic hypoxia could be a new treatment strategy for obesity-induced NAFLD.
DOI: 10.1016/j.lfs.2020.117633

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

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
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

Diseases ID DO ID Disease Name Definition Class
I14 9970 Obesity An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition Details

Drug ID Drug Name Type DrugBank ID Targets Category Latest Progress
D201 L-Carnitine Supplement DB00583 SLC22A4; SLC22A5; CRAT; MPO -- Under clinical trials Details
D579 Emfilermin Miscellany -- adipocytes Enhance lipid metabolism Under investigation Details
D062 Carnitine complex Supplement DB00583 SLC22A4; SLC22A5; CRAT; MPO -- Under clinical trials Details