All Phenotypes Slc16a3<em1Gpt> MGI Mouse

decreased susceptibility to atherosclerosis ( J:357567 )

• mice fed a high fat diet (HFD) for 12 weeks show a significant reduction in lipid content, necrotic core, atherosclerotic plaque area and mRNA expression of Itgam (integrin alpha M, aka Cd11b) in the plaque, but greater aortic collagen content than HFD-fed mice homozygous only for Apoe^em1Gpt and Slc16a3^em1Gpt, suggesting a delay in atherosclerosis progression

• arteries of HFD-fed mice show a further elevation of the lactylation modifier EP300 (E1A binding protein p300), pan-lysine lactylation (Pan Kla), and H3 lysine 18 lactylation (H3K18la) with increased macrophage H3K18la in the aortic root relative to HFD-fed mice only homozygous for Apoe^em1Gpt and Slc16a3^em1Gpt

• arteries from HFD-fed mice show decreased mRNA expression of proinflammatory genes (Il6, Il1b, Tnf) and increased mRNA expression of anti-inflammatory genes (Arg1, Il10, Tgfb1) relative to arteries from HFD-fed mice only homozygous for Apoe^em1Gpt and Slc16a3^em1Gpt

increased susceptibility to atherosclerosis ( J:357567 )

• after treatment with C646 (an EP300 inhibitor), HFD-fed mice show a significant increase in atherosclerotic plaque area along with a reduction in the expression of H3K18la and of reparative genes (Arg1, Il10, Mrc1, Tgfb1, Pdha1, Idh2, Sdha, and Fh1) relative to vehicle-treated HFD-fed controls

abnormal macrophage physiology ( J:357567 )

• bone marrow-derived macrophages (BMDMs) from HFD-fed mice show increased cellular oxygen consumption rate (OCR) and decreased extracellular acidification rate (ECAR) relative to BMDMs from HFD-fed mice only homozygous for Apoe^em1Gpt and Slc16a3^em1Gpt

increased circulating interleukin-10 level ( J:357567 )

• HFD-fed mice show significantly higher serum IL-10 levels than HFD-fed mice only homozygous for Apoe^em1Gpt and Slc16a3^em1Gpt

decreased circulating interleukin-6 level ( J:357567 )

• HFD-fed mice show significantly lower serum IL-6 levels than HFD-fed mice only homozygous for Apoe^em1Gpt and Slc16a3^em1Gpt

decreased circulating tumor necrosis factor level ( J:357567 )

• HFD-fed mice show significantly lower serum TNF-alpha levels than HFD-fed mice only homozygous for Apoe^em1Gpt and Slc16a3^em1Gpt

abnormal aerobic respiration ( J:357567 )

• arteries from HFD-fed mice show decreased mRNA expression of glycolysis genes (Hk2 and Ldha) relative to arteries from HFD-fed mice only homozygous for Apoe^em1Gpt and Slc16a3^em1Gpt

abnormal epigenetic regulation of gene expression ( J:357567 )

• BMDMs from HFD-fed mice show a significant increase in the enrichment of H3 lysine 18 lactylation (H3K18la) at the promoters of reparative genes, including anti-inflammatory genes and TCA cycle genes (Arg1, Il10, Mrc1, Tgfb1, Pdha1, Idh2, Sdha, and Fh1) relative to BMDMs from HFD-fed mice only homozygous for Apoe^em1Gpt and Slc16a3^em1Gpt

• after treatment with C646 (an EP300 inhibitor), BMDMs from HFD-fed mice show a significant reduction in the enrichment of H3K18la at macrophage reparative gene promoters

abnormal mitochondrial physiology ( J:357567 )

• BMDMs from HFD-fed mice show increased cellular oxygen consumption rate (OCR) and decreased extracellular acidification rate (ECAR) relative to BMDMs from HFD-fed mice only homozygous for Apoe^em1Gpt and Slc16a3^em1Gpt

• moreover, arteries from HFD-fed mice show decreased mRNA expression of glycolysis genes and increased mRNA expression of tricarboxylic acid (TCA) cycle genes, suggesting improved mitochondria function

abnormal tricarboxylic acid cycle ( J:357567 )

• arteries from HFD-fed mice show increased mRNA expression of tricarboxylic acid (TCA) cycle genes (Pdha1, Idh2, Sdha, and Fh1) relative to arteries from HFD-fed mice only homozygous for Apoe^em1Gpt and Slc16a3^em1Gpt