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  • While it is known that circulating LDL C levels

    2023-01-18

    While it is known that circulating LDL-C levels are largely regulated by either controlling the rate of hepatic production of its triglyceride-rich precursor VLDL particle or the rate of LDLR-mediated LDL particle clearance [58], it should be noted that important differences exist between rodents and humans. Studies in rodents show that when Oxaliplatin are consumed in excess of caloric requirements, elevated insulin and blood glucose stimulate hepatic and subsequent esterification of fatty acids to form triglycerides for storage in the liver, or transport via plasma VLDL to white adipose tissue for fat storage [59]. As such, the suppression of hepatic DNL in rodents has been reported Oxaliplatin to promote marked reductions in plasma triglycerides [59]. By contrast, DNL in healthy humans on a balanced diet appears to be relatively low, contributing only approximately 5–10% of the hepatic VLDL triglyceride pool with the majority of fatty acids coming from dietary sources and peripheral lipolysis[60]. Furthermore, in another study of subjects receiving a diet supplemented with excess carbohydrate, glucose was found to be oxidized at the expense of fatty acids, rather than being converted into fatty acids and triglycerides for storage or secretion into the blood via VLDL [61]. Therefore, in contrast to rodents, the suppression of hepatic DNL in healthy humans might not significantly impact plasma triglycerides. However, because liver DNL is upregulated in individuals with hepatic insulin resistance 62, 63, 64, 65 or presenting with NAFLD (see the following section) [66], inhibition of DNL might lead to reduced plasma triglycerides in such patients, but this remains to be further explored.
    DNL and NAFLD: A Rationale for Using ACL Inhibitors?
    ACL Inhibition in the Liver via Bempedoic Acid (BA) Significant clinical evidence supporting the therapeutic utility of pharmacological ACL inhibition has recently been generated by investigational use of BA. Although not prospectively pursued as an ACL inhibitor in cell-free assays, BA was discovered and optimized in a phenotypic screen where α-substituted dicarboxylic acids were evaluated based on potency for concomitant inhibition of de novo cholesterol and fatty acid synthesis [105]. Subsequent studies confirmed these effects in primary human liver cells and established that BA could inhibit lipid synthesis via ACL inhibition 52, 106. Using siRNA-mediated suppression of very long-chain acyl-CoA synthetase (ACSVL1; gene: Slc27a2), BA was revealed as a prodrug requiring ACSVL1-dependent intracellular CoA activation to inhibit ACL 52, 107. In vivo studies in rats showed that BA treatment reduced levels of hepatic acetyl-CoA and malonyl-CoA [106], and given that malonyl-CoA is an allosteric inhibitor of CPT-1, it also increased rates of fatty acid β-oxidation 52, 105, 106. Consistent with ACL inhibition, BA promoted hypolipidemic effects in a variety of disease models such as dyslipidemic hamsters and obese Zucker rats 105, 106, and attenuated atherosclerosis and serum amyloid A in high-fat, high-cholesterol-fed and , frequently used as models for hyperlipidemia and associated ASCVD 52, 97, 106. In mice, BA treatment reduced liver cholesterol mass, upregulated LDLR expression, and lowered plasma LDL-C [52]. In insulin-resistant mice, BA treatment reduced plasma cholesterol, VLDL-C, LDL-C, and triglycerides [97]. Although the effect of BA in reducing plasma LDL-C levels was consistent with previous reports of statins in mice [108], this effect might also be linked to inhibition of fatty acid synthesis leading to reduced production of the LDL particle precursor VLDL, a pathway known to be increased by insulin resistance 58, 77. Further examination of liver and other metabolic outcomes in mice showed that BA also reduced diet-induced hepatic inflammatory gene expression (e.g., Tnf, Ccl3, and Nos2) and improved glucose tolerance [97]. To determine the therapeutic potential of BA in NASH, additional studies are warranted using models that can present informative histological endpoints, including hepatic ballooning and fibrosis.