Short chain acyl-CoA dehydrogenase deficiency and short-term high-fat diet perturb mitochondrial energy metabolism and transcriptional control of lipid-handling in liver
Year: 2016
Type: article
Abstract: BACKGROUND: The liver is an important site of fat oxidation, which participates in the metabolic regulation of food intake. We showed previously that mice with genetically inactivated Acads, encoding short-chain acyl-CoA dehydrogenase (SCAD), shift food consumption away from fat and toward carbohydrate when tested in a macronutrient choice paradigm. This phenotypic eating behavior suggests a link between fat oxidation and nutrient choice which may involve an energy sensing mechanism. To identify hepatic processes that could trigger energy-related signals, we have now performed transcriptional, metabolite and physiological analyses in Acads-/- mice following short-term (2 days) exposure to either high- or low-fat diet. METHODS AND RESULTS: Metabolite analysis revealed 25 acylcarnitine species that were altered by diet and/or genotype. Compared to wild-type mice, phosphorylated AMP-activated protein kinase was 40 % higher in Acads-/- mice after short-term high-fat diet, indicating a low ATP/AMP ratio. Metabolite analyses in isolated liver mitochondria from Acads-/- mice during ADP-linked respiration on butyrate demonstrated a reduced oxygen consumption rate (OCR) compared to wild-type, an effect that was not observed with succinate or palmitoylcarnitine substrates. Liver transcriptomic responses in Acads-/- mice fed high- vs. lowfat diet revealed increased RXR/PPARA signaling, up-regulation of lipid handling pathways (including beta and omega oxidation), and increased mRNA expression of Nfe2l2 target genes. CONCLUSIONS: Together, these results point to an oxidative shortage in this genetic model and support the hypothesis of a lower hepatic energy state associated with SCAD deficiency and high-fat diet.
Source: Nutrition & Metabolism
Authors: Sujoy Ghosh, Claudia Kruger, Shawna Wicks, Jacob Simon, K. Ganesh Kumar, William D. Johnson, Randall L. Mynatt, Robert C. Noland, Brenda K. Richards
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,590
Funders: American Heart Association, University of Michigan, Louisiana Clinical and Translational Science Center, National Institutes of Health, Nutrition Obesity Research Center, University of North Carolina, Medical Research Council, National Medical Research Council, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Complementary and Integrative Health
Awards: G1051323641, G142261553, G1686704458, G1863416421, G1937633654, G2353154098, G2600557702, G305254594, G331990242, G3334739079, G3495878012, G3667826151, Mentoring Obesity and Diabetes Research in Louisiana, G4727336216, G4948298336, Pennington/Louisiana NORC - Supplement NOT-OD-21-089, G5806042018, G5850863802, G5950577451, Louisiana Clinical and Translational Science Center, G7096375459, Defining the role of skeletal muscle peroxisomes in glucose homeostasis, G799249705, G84614345, G8477750575, G9000054552, G9000059149, G9000092754, G9000097295, G9000133560, G9000311072
OpenAlex ID: W2290798995