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Abstract Details
Pharmacologic inhibition of lipogenesis for the treatment of NAFLD
J Hepatol. 2023 Nov 15:S0168-8278(23)05275-3. doi: 10.1016/j.jhep.2023.10.042.Online ahead of print.
1Internal Medicine Research Unit, Pfizer Worldwide Research Development and Medical, Cambridge, MA 02139. Electronic address: william.esler@pfizer.com.
2Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115. Electronic address: dcohen@bwh.harvard.edu.
Abstract
The hepatic accumulation of excess triglycerides is a seminal event in the initiation and progression of non-alcoholic fatty liver disease. Hepatic steatosis occurs when the hepatic accrual of fatty acids by uptake from the plasma and by de novo lipogenesis (DNL) is no longer balanced by rates of fatty acid oxidation and by secretion as VLDL triglycerides. Accumulating data indicate that increased rates of DNL are central to the development of hepatic steatosis in NAFLD. Whereas the main drivers in NAFLD are transcriptional, owing to both hyperinsulinemia and hyperglycemia, the effectors of DNL are a series of well characterized enzymes. Several have proven amenable to pharmacologic inhibition or oligonucleotide-mediated knock down, with lead compounds that have been advanced to phase 2 clinical trials. These have largely proven effective. In human subjects with NAFLD, percent reductions in liver fat have closely mirror percent inhibition of DNL, thereby affirming the critical contributions of DNL to NAFLD pathogenesis. The safety profiles of these compounds have so far remained encouraging. It is anticipated that inhibitors of DNL, when administered alone or in combination with other therapeutic agents, will become important agents in the management of human NAFLD.