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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/220570
Study of new strategies for steatotic liver disease: SIRT1-mediated modulation of VLDLR levels and evaluation of a soluble epoxyde hydrolase-targeted PROTAC
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[eng] Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease (CLD). The first stage in the development of MASLD is metabolic dysfunction-associated fatty liver (MASL), which is defined as a condition where excessive levels of triglycerides (TG) accumulate in the liver. Little is known about the role played by the uptake of lipoproteins, such as very low-density lipoproteins (VLDL) that predominantly transport TG in plasma, in the development of hepatic steatosis. Interestingly, endoplasmic reticulum (ER) stress-mediated increase in the levels of the VLDL receptor (VLDLR) results in remarkable hepatic steatosis via enhanced triglyceride-rich lipoprotein delivery to the liver. A better understanding of how hepatic VLDLR is regulated might help to develop new effective therapies against MASLD. On the other hand, soluble epoxide hydrolase (sEH), an enzyme highly expressed in the liver, converts epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFAs) to their corresponding diols. These diols are much less bioactive than their parents’ epoxides. As a result, compounds that inhibit sEH increase the levels of EETs and other EpFAs, which are opposing counterparts to the largely pro-inflammatory prostanoids and leukotrienes, thereby providing therapeutic efficacy for the treatment of several diseases, including hepatic steatosis. An additional new strategy for targeting sEH might be the use of proteolysis-targeting chimeras (PROTACs), due to its capacity to induce its degradation.
In the present thesis, we show that induction of hepatic steatosis by fructose-drinking water in rats caused a reduction in the levels of hepatic sirtuin 1 (SIRT1), a NAD (+)-dependent deacetylase, and upregulation of VLDLR, suggesting a potential relationship between these two proteins. Consistent with this, Sirt1-/- mice displayed increased hepatic VLDLR levels and enhanced expression of HIF-1α-target genes. Likewise, the increase in VLDLR protein levels induced by pharmacological inhibition or gene knockdown of SIRT1 in a human hepatic cell line was abolished by a HIF-1α inhibitor. Moreover, SIRT1
activation in mice prevented the increase in hepatic VLDLR protein levels caused by ER stress. Additionally, we report that the sEH-targeting PROTAC ALT-PG2 degrades this protein in the human hepatoma-derived Huh-7 cell line and in primary mouse hepatocytes as well as in the liver of mice. PROTAC-mediated degradation of the sEH protein in cells resulted in adenosine monophosphate-activated protein kinase (AMPK) activation, while phosphorylated extracellular-signal-regulated kinase 1/2 (ERK1/2) was reduced. Consistent with the role of these two kinases in ER stress, ALT-PG2 reduced both ER stress and inflammatory markers.
Altogether, the findings of the present doctoral thesis shed light on a new mechanism of VLDLR regulation and its contribution to hepatic steatosis and demonstrate that targeting sEH with a PROTAC molecule is an effective strategy to activate AMPK and to prevent ER stress and inflammation in hepatic cells.
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PEYMAN, Mona. Study of new strategies for steatotic liver disease: SIRT1-mediated modulation of VLDLR levels and evaluation of a soluble epoxyde hydrolase-targeted PROTAC. [consulta: 3 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/220570]