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. 2020 Oct 1;42:101092. doi: 10.1016/j.molmet.2020.101092

Figure 1.

Figure 1

A summary of hepatic lipid metabolism pathways altered in NAFLD and driving dyslipidemia. Increased hepatic TG in NAFLD is a result of several processes. Elevated plasma insulin and glucose levels respectively activate the LXR and ChREBP pathways, which increase de novo lipogenesis (DNL). Through the action of ACC, DNL increases the concentration of malonyl-coA, leading to inhibition of CPT1 and consequently reducing fatty acid oxidation (FAO) and mitochondrial function. In parallel, LXR increases the expression of ANGPTL8 and 3, two inhibitors of LPL. Moreover, ANGPTL8 contributes to increase hepatic TG by decreasing intracellular TG hydrolysis via inhibiting ATGL. Increased hepatic TG content leads to higher TG secretion and, as a consequence, increased plasma TG levels. Increased intracellular cholesterol in the liver inhibits the SREBP2 pathway. SREBP2 increases LDLR and PCSK9 mRNA expression. These changes combined with additional post-transcriptional regulation of PCSK9 lead to reduced membrane-bound LDLR, which leads to decreased LDL uptake by the liver. The ensemble of these changes contribute to increased large VLDL1 and the formation of small dense LDL, which favors foam cell formation and ultimately atherosclerosis. A number of potential NASH therapies directly target metabolic pathways of lipid metabolism. For example, firsocostat inhibits ACC, reducing DNL and hepatic TG accumulation. Statins inhibit HMGCoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Other strategies focus on activating different nuclear receptors that more broadly control lipid and glucose metabolism. These include nuclear receptors from the PPAR family, FXR and TR-β. Among those treatments, fibrates are PPARα agonists, pegbelfermin is a FGF21 analog (a PPARα target gene), thiazolidinediones (pioglitazone and rosiglitazone) are PPARγ agonists, elafibranor is a dual-PPARα/δ agonist, lanifibranor is a pan-PPAR agonist, obeticholic acid (OCA) is an FXR agonist, NGM282 is an FGF19 analog (FXR target gene in the intestine), and resmetirom is a TR-β agonist.