SAT-697 - The Therapeutic Effect of PEMT on Mitochondrial Function and Lipid Remodeling in A Mouse Model of MASH Is Blocked by Thiazolidinedione-Mediated Pparγ Activation.

Metabolic Dysfunction-Associated Steatohepatitis (MASH) is prevalent in patients with obesity and type 2 diabetes. Despite its potential as a treatment, activating peroxisome proliferator-activated receptor gamma (PPARγ) with thiazolidinediones (TZD) to reduce insulin resistance, hepatic inflammation, and fibrosis has shown inconsistent hepatic clinical outcomes. We previously reported an association between hepatocyte PPARγ expression, the onset of MASH, and reduced expression of hepatic phosphatidylethanolamine methyltransferase (PEMT). PEMT methylates phosphatidylethanolamine (PE) into phosphatidylcholine (PC) which modulates membrane composition and enhances very low-density lipoproteins (VLDL) production. The negative association between PPARγ and PEMT is highly relevant, as patients with MASH have increased PPARγ expression and reduced PEMT expression in the liver, and loss-of-function PEMT SNPs, are associated with MASH. Here, we have restored hepatocyte PEMT expression in mice that develop diet-induced MASH with fibrosis. After 20 weeks of diet, we restored hepatocyte PEMT expression (Pemt-Hep) using an AAV8-TBG-Pemt and treated the mice with TZD (rosiglitazone) for 8 weeks to reverse MASH. Diet-induced MASH was associated with obesity and hepatic mitochondrial dysfunction, characterized by reduced mitochondrial content, decreased levels of oxidative phosphorylation complexes (OXPHOS), and reduced ATP production. Diet-induced MASH also reduced the expression of genes involved in PE synthesis in the Kennedy pathway, which preferentially incorporate long-chain polyunsaturated fatty acids (PUFA). Pemt-Hep increased PEMT expression, VLDL secretion, mitochondrial content, and OXPHOS levels, to significantly reduce steatosis. LC/MS targeted lipidomic analysis showed that Pemt-Hep increased the levels of PC-containing long-chain omega3-PUFA: 16:0/22:5, 18:2/22:5, 20:4/22:6. In contrast, TZD did not reduce steatosis nor MASH, despite reducing plasma lipid levels, insulin resistance, and the expression of hepatic genes involved in inflammation and fibrosis. In fact, TZD may impair fatty acid oxidation because there was an increase in plasma ketone levels and hepatic OXPHOS complex II activity, but a reduction in ATP production, concomitant with increased levels of PC and PE containing 16:0, 16:1, and 18:1, indicative of increased de novo lipogenesis. Furthermore, TZD blocked the positive effects derived from Pemt-Hep on VLDL production, mitochondrial function, and PC containing long-chain omega3 PUFA. Taken together, hepatocyte PEMT reduced steatosis by increasing the levels of PC-containing omega3 PUFA and improving mitochondrial function. However, these therapeutic effects on liver function were blocked by the TZD-mediated activation of PPARγ, which may account for the limited potential of TZD for the treatment of MASH.

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