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Differential Effects of De Novo Lipogenesis Inhibitors on plasma lipids and liver PNPLA3
Author(s) -
pocai alessandro
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.487.17
Subject(s) - lipogenesis , steatohepatitis , fatty liver , endocrinology , medicine , fibrosis , liver disease , cd36 , steatosis , lipid metabolism , biology , chemistry , disease , receptor
Obesity and genetic polymorphisms such as the patatin‐like phospholipase domain‐containing 3 (PNPLA3‐I148M; 49% allele frequency in Hispanics) predispose to non‐alcoholic steatohepatitis (NASH). NASH patients are at increased risk of death by cardiovascular and liver‐related complications. Hence, there is an urgent need to develop new strategies for preventing and treating NASH. Increased de novo lipogenesis (DNL) and liver lipid deposition are processes associated with the early stage of the disease. Inhibition of liver acetyl‐CoA carboxylase (ACCi) in NASH patients reduces DNL and liver triglycerides (TG) and improves noninvasive markers of fibrosis. Unexpectedly, ACCi results in a significant rise in plasma TG, a major concern given the already high risk of CV disease in NASH patients. Hence, alternative strategies to reduce DNL devoid of the lipid liability might be beneficial for liver steatosis in NASH. Previous studies have demonstrated that diacylglycerol acyltransferase 2 inhibition (DGAT2i) lowers DNL and improves inflammation and fibrosis in rodents. Here, we conducted a 2‐week study in diet‐induced obese (DIO) mice comparing the effects of ACCi versus DGAT2i on lipid metabolism. Thirty‐six DIO mice were treated with vehicle, ACCi (30 mg/kg PO) or DGAT2i (10 mg/kg and 30 mg/kg PO). ACCi and DGAT2i resulted in significant reduction in liver fat mass (−43% for ACCi vs. −23 and −29% for DGAT2i), however, ACCi significantly increased plasma TG (+49%, ACCi treatment vs. vehicle; p < 0.001). ACCi increased mRNA expression of liver sterol regulatory element‐binding protein 1c (SREBP‐1c, +40%) and of the lipogenic genes stearoyl‐CoA desaturase‐1 (SCD1; +650%), ELOVL fatty acid elongase 6 (ELOVL6; +373%), and Glycerol‐3‐phosphate acyltransferase 1 (GPAT1; +96.4 %). In the same study, DGAT2i resulted in no change of plasma TG while reducing expression of SCD1 (−92% and −95%), ELOVL6 (−16% and −10%) and GPAT1 (−32% and −39%) mRNA. DGAT2i decreased PNPLA3 expression (−71% and −79%; DGAT2i 10 and 30 mg/kg vs . vehicle; p <0.05) while ACCi increased PNPLA3 (+2400%, ACCi vs. vehicle; p <0.001). PCSK9 plasma levels were significantly reduced (−67%; p < 0.001) in DGAT2i treated mice. In contrast, ACCi treated mice exhibited a significant increase of plasma PCSK9 levels (226%; p < 0.001). Inhibition of de novo lipogenesis with DGAT2 and ACC inhibitors are potential promising strategies to lower liver lipids in NASH patients. Our results also demonstrated that DGAT2i and ACCi inhibition have opposite effects on liver PNPLA3 and plasma PCSK9 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .