Hypertriglyceridemia in chronic kidney disease: pathophysiological mechanisms, cardiovascular risk, and emerging therapeutics

Fig. 1. The action sites of traditional TG-regulating drugs. Fibrate drugs activate PPARα, enhancing fatty acid oxidation and reducing TG levels. Statins inhibit HMG-CoA reductase, thereby suppressing cholesterol synthesis and indirectly reducing the secretion of VLDL. PPARα. HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A.‌ Source: Created with BioRender.com

Fig. 2. Mechanisms of omega-3 fatty acids reduce hepatic TG synthesis. EPA/DHA activate nuclear receptor FXR to inhibit the activity of transcription factor SREBP-1c and directly inhibit the key synthetic enzyme DGAT in the cytoplasm, jointly reducing TG production. EPA. DHA. FXR, Farnesoid X Receptor. SREBP-1c, Sterol Regulatory Element-binding protein-1c. DGAT, Diacylglycerol Acyltransferase. Solid arrows represent activation or metabolic flux; Red “×” represents inhibition. Source: Created with BioRender.com

Fig. 3. The mechanism of action of gene therapy targeting ApoC-III. This figure illustrates the novel gene therapy targeting ApoC-III, in which ASO bind to ApoC-III mRNA and recruit ribonuclease H1 for its degradation, reducing ApoC-III protein synthesis. Source: Created with BioRender.com

Fig. 4. Therapeutic strategies to inhibit ANGPTL3 function. This figure compares two approaches targeting ANGPTL3. (Left) GalNAc-conjugated siRNA against ANGPTL3 is taken up by hepatocytes and silences ANGPTL3 mRNA through the RNA-induced silencing complex, reducing protein synthesis. (Right) The monoclonal antibody evinacumab binds to and neutralizes circulating ANGPTL3 protein. Both strategies alleviate ANGPTL3-mediated inhibition of LPL. This enhances the hydrolysis of TGs in VLDL and IDL, promoting their clearance via hepatic receptors. Source: Created with BioRender.com

Fig. 5. Mechanism of PCSK9 inhibitors. PCSK9 inhibitors neutralize circulating PCSK9, preventing its binding to hepatic LDL receptors. This reduces receptor degradation and promotes receptor recycling to the cell surface, thereby enhancing LDL-C uptake and clearance. Source: Created with BioRender.com

Fig. 6. The role of the gut microbiota-lipid-kidney axis in the progression of CKD. Dysbiosis of the gut microbiota can lead to an increase in harmful metabolites (such as TMAO, LPS) and a decrease in beneficial metabolites (such as short-chain fatty acids), thereby promoting systemic inflammation, abnormal lipid metabolism, and increased production of VLDL. These factors collectively contribute to lipid deposition, inflammatory response, and renal fibrosis, forming a vicious cycle. As kidney function deteriorates, the accumulated uremic toxins (such as indoxyl sulfate) can further impair intestinal barrier function, exacerbating microbiota dysbiosis.Source: Created with BioRender.com