Research Article Details

Article ID: A16161
PMID: 28529818
Source: J Diabetes Metab
Title: High protein/fish oil diet prevents hepatic steatosis in NONcNZO10 mice; association with diet/genetics-regulated micro-RNAs.
Abstract: OBJECTIVE: NONcNZO10 (NZ10) mice are predisposed to obesity and develop type 2 diabetes (T2D) and hepatic steatosis even when maintained on a control diet (CD) of 6% fat. Studies were designed to determine whether this extreme susceptibility phenotype could be alleviated by diet and if so the molecular targets of diet. METHODS: NZ10 and SWR/J (SWR) control mice were fed a CD or a test diet of high protein and fish oil (HPO) for 19 weeks and then analyzed for steatosis, blood chemistry, hepatic gene and micro-RNA expression. RESULTS: HPO diet prevented steatosis, significantly increased serum adiponectin and reduced serum cholesterol and triglycerides only in NZ10 mice. The HPO diet repressed hepatic expression of fatty acid metabolic regulators including PPAR-γ, sterol regulatory element-binding protein-c1, peroxisome proliferator-activated receptor gamma co-activator-1, fatty acid synthase, fatty acid binding protein-4, and apolipoprotein A4 genes only in NZ10 mice. Also repressed by a HPO diet were adiponectinR2 receptor, leptin-R, PPAR-α, pyruvate dehydrogenase kinase isoforms 2 and 4, AKT2 and GSK3β. Micro-RNA (miR) arrays identified miRs that were diet and/or genetics regulated. QRTPCR confirmed increased expression of miR-205 and suppression of a series of miRs including miRs-411, 155, 335 and 21 in the NZ10-HPO group, each of which are implicated in the progression of diabetes and/or steatosis. Evidence is presented that miR-205 co-regulates with PPARγ and may regulate fibrosis and EMT during the progression of steatosis in the livers of NZ10-CD mice. The dietary responses of miR-205 are tissue-specific with opposite effects in adipose and liver. CONCLUSION: The results confirm that a HPO diet overrides the genetic susceptibility of NZ10 mice and this correlates with the suppression of key genes and perhaps micro-RNAs involved in hyperglycemia, dyslipidemia and inflammation including master PPAR regulators, adiponectin and leptin receptors.
DOI: 10.4172/2155-6156.1000676

Strategy ID Therapy Strategy Synonyms Therapy Targets Therapy Drugs
S03 Anti-fibrosis fibrosis Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 Details

Target ID Target Name GENE Action Class UniProtKB ID Entry Name
T10 Caspase-1 CASP1 inhibitor Enzyme P29466 CASP1_HUMAN Details
T20 Fatty acid synthase FASN inhibitor Enzyme P49327 FAS_HUMAN Details
T05 Peroxisome proliferator-activated receptor gamma PPARG agonist Nuclear hormone receptor P37231 PPARG_HUMAN Details

Diseases ID DO ID Disease Name Definition Class
I13 3146 Lipid metabolism disorder An inherited metabolic disorder that involves the creation and degradation of lipids. http://en.wikipedia.org/wiki/Lipid_metabolism disease of metabolism/ inherited metabolic disorder Details
I05 9352 Type 2 diabetes mellitus A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus Details
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
D328 Serine Chemical drug DB00133 SRR Improve insulin resistance Under clinical trials Details
D137 Fish oil Biological drug DB13961 -- -- Under clinical trials Details
D579 Emfilermin Miscellany -- adipocytes Enhance lipid metabolism Under investigation Details