4-HNE, 4-hydroxynonenal
The clinical translation of these trial results, which will be important for the comparison of GLP-1RAs with SGLT2 inhibitors in the treatment of patients with heart failure and a preserved ejection fraction, remains to be determined.470,478,482,483,484 GLP-1RAs in the digestive system Treatment with GLP-1RAs can alleviate insulin signaling by reducing the phosphorylation of Akt protein (Decreased Akt-P) and activating Protein Kinase C- (PKC-).485,486 This affects the synthesis of triacylglycerol (TAG), phosphatidic acid (di-P PA), and diacylglycerol (DAG) in the liver.206,487 These changes lead to a reduction in the production of non-esterified fatty acids (LCFAs) and glucose, as well as a decrease in the synthesis of VLDL (Very Low-Density Lipoprotein).3 GLP-1RAs and NAFLD/NASH When dietary nutrients are ingested, endogenous incretins (GIP and GLP-1) activate K and L cells in the gut, which then secrete GIP and GLP-1.488,489,490 In the pancreas, this stimulates the secretion of insulin and inhibits the secretion of glucagon.491 In the brain, it reduces appetite and improves satiety.130,133 In the gastrointestinal tract, it lowers the synthesis and secretion of triglycerides.491 By regulating appetite, insulin secretion, and lipid metabolism, GLP-1RAs have potential benefits in the treatment of NAFLD, NASH, and T2DM.130,492,493 NASH is a liver disease primarily caused by fat accumulation, which can progress to liver fibrosis, cirrhosis, or even liver cancer.494,495,496,497,498 The role of GLP-1 in NASH has garnered attention due to its potential in regulating metabolism, improving insulin sensitivity, and exerting anti-inflammatory effects.17,499,500,501,502,503 Insulin resistance, a common occurrence in NASH patients, is a key driver of the diseases progression.504,505,506 GLP-1 enhances the insulin signaling pathway in the liver by activating the GLP-1R, especially through the phosphorylation of insulin receptor substrates and the activation of the PI3K/Akt signaling pathway, thereby increasing hepatic insulin sensitivity, facilitating glucose uptake and utilization, and reducing hepatic gluconeogenesis.3,507 GLP-1RAs reduce liver fat accumulation by activating AMPK, which inhibits fatty acid synthesis enzymes and promotes fatty acid -oxidation, thus diminishing lipid droplet accumulation in hepatocytes.508,509,510,511 Additionally, GLP-1 mitigates liver inflammation and fibrosis by inhibiting the NF-B pathway, reducing the release of pro-inflammatory cytokines such as TNF- and IL-6, and thus suppressing inflammatory pathways.307,413 In terms of apoptosis inhibition, GLP-1 activates the PI3K/Akt signaling pathway, enhances the expression of the anti-apoptotic protein Bcl-2, and inhibits the activation of caspase family proteins, reducing cell apoptosis.206 This helps prevent the progression of NASH to liver fibrosis and cirrhosis
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