High Fat Activates O-GlcNAcylation and Affects AMPK/ACC Pathway to Regulate Lipid Metabolism

Abstract

A high-fat diet often leads to excessive fat deposition and adversely affects the organism. However, the mechanism of liver fat deposition induced by high fat is still unclear. Therefore, this study aimed at acetyl-CoA carboxylase (ACC) to explore the mechanism of excessive liver deposition induced by high fat. In the present study, the ORF of ACC1 and ACC2 were cloned and characterized. Meanwhile, the mRNA and protein of ACC1 and ACC2 were increased in liver fed with a high-fat diet (HFD) or in hepatocytes incubated with oleic acid (OA). The phosphorylation of ACC was also decreased in hepatocytes incubated with OA. Moreover, AICAR dramatically improved the phosphorylation of ACC, and OA significantly inhibited the phosphorylation of the AMPK/ACC pathway. Further experiments showed that OA increased global O-GlcNAcylation and agonist of O-GlcNAcylation significantly inhibited the phosphorylation of AMPK and ACC. Importantly, the disorder of lipid metabolism caused by HFD or OA could be rescued by treating CP-640186, the dual inhibitor of ACC1 and ACC2. These observations suggested that high fat may activate O-GlcNAcylation and affect the AMPK/ACC pathway to regulate lipid synthesis, and also emphasized the importance of the role of ACC in lipid homeostasis.

O‐GlcNAcylation promotes fatty acid synthase activity under nutritional stress as a pro‐survival mechanism in cancer cells

“…Previous investigations of the link between O‐GlcNAcylation and fatty acid metabolism have largely focused on upstream pathways including AMPK and mTORC1 signalling, as well as transcriptional regulation of FASN through the regulation of transcription factors and FASN stability [38,41–43]. In particular, transcription factors such as carbohydrate‐responsive element‐binding protein (ChREBP) and sterol regulatory element‐binding protein 1c (SREBP1c) have been reported to be activated by O‐GlcNAcylation, thereby enhancing FASN expression [41,44,45].…”

Endoplasmic Reticulum Stress Disturbs Lipid Homeostasis and Augments Inflammation in the Intestine and Isolated Intestinal Cells of Large Yellow Croaker (Larimichthys crocea)

“…The TG content was analyzed according to a previous study (20). After TM treatment for 12 h, cells were incubated with BODIPY 493/503 (Sigma) for 10 min, washed with phosphate buffer solution (PBS, Solarbio) three times, and then immediately observed lipid droplets in the cells with a fluorescent microscope (Nikon, Japan), according to the methods in a previous study (21).…”

A nexus of lipid and O-Glcnac metabolism in physiology and disease

“…By contrast, PA led to a 50% decrease in the O- GlcNAcylation of SHSY-5Y human neuroblastoma cells, mimicking the similar effect of HFD on the hippocampus ( 12 ). Oleate (OA), an endogenously abundant unsaturated LCFA, was reported to drive protein O- GlcNAcylation in primary hepatocytes from fish ( 31 ) and rat neonatal cardiomyocytes ( 32 ). Importantly, LCFA concentrations in these experiments, 100-600 uM PA or 400-800 uM OA, were within the physiological range for human plasma ( 33 ) although the durations of exposure varied widely by experiment, from 2 to 48 hours (see Supplementary Table S1 for study details).…”

“…Data from in vitro experiments is more preliminary but suggests that lipid regulation of OGT and OGA is less direct than for F6P and HBP enzymes. Two studies found increased OGT/ogt mRNA following LCFA exposures – with PA in human gastric cancer cells ( 28 ) or OA in primary hepatocytes from yellow croaker fish ( 31 ). However, PA in mouse liver and macrophage cells had no effect on transcription of Ogt or Oga ( 25 , 26 ).…”