Fatty Acid Synthase–Suppressor Screening Identifies Sorting Nexin 8 as a Therapeutic Target for NAFLD

Abstract

BaCKgRoUND aND aIMS: NAFLD is the most prevalent chronic liver disease without any Food and Drug Administration-approved pharmacological intervention in clinic. Fatty acid synthase (FASN) is one of the most attractive targets for NAFLD treatment because of its robust rate-limiting capacity to control hepatic de novo lipogenesis. However, the regulatory mechanisms of FASN in NAFLD and potential therapeutic strategies targeting FASN remain largely unknown. MetHoDS aND ReSUltS:Through a systematic interactomics analysis of FASN-complex proteins, we screened and identified sorting nexin 8 (SNX8) as a binding partner of FASN. SNX8 directly bound to FASN and promoted FASN ubiquitination and subsequent proteasomal degradation. We further demonstrated that SNX8 mediated FASN protein degradation by recruiting the E3 ligase tripartite motif containing 28 (TRIM28) and enhancing the TRIM28-FASN interaction. Notably, Snx8 interference in hepatocytes significantly deteriorated lipid accumulation in vitro, whereas SNX8 overexpression markedly blocked hepatocyte lipid deposition. Furthermore, the aggravating effect of Snx8 deletion on NAFLD was validated in vivo as hepatic steatosis and lipogenic pathways in the liver were significantly exacerbated in Snx8-knockout mice compared to wild-type controls. Consistently, hepatocytespecific overexpression of Snx8 in vivo markedly suppressed high-fat, high-cholesterol diet (HFHC)-induced hepatic steatosis. Notably, the protective effect of SNX8 against NAFLD was largely dependent on FASN suppression.CoNClUSIoNS: These data indicate that SNX8 is a key suppressor of NAFLD that promotes FASN proteasomal degradation. Targeting the SNX8-FASN axis is a promising strategy for NAFLD prevention and treatment. (Hepatology 2021;74:2508-2525. N AFLD has become the most prevalent chronic liver disease and affects >25% of the population worldwide. (1,2) Hepatic steatosis is the major characteristic of NAFLD and promotes the progression of fatty liver to a more advanced

Novel Insights into the Differences in Nutrition Value, Gene Regulation and Network Organization between Muscles from Pasture-Fed and Barn-Fed Goats

“…Interestingly, diverse lncRNAs that target genes related to NAFLD were identified in our study. NAFLD is caused by a build-up of fat in the liver and mainly occurs in people who are overweight or obese [47]. The target genes of the lncRNAs are mainly enriched in the Oxidative phosphorylation, EGFR tyrosine kinase inhibitor resistance and MAPK signaling pathway, which is related to diverse functions such as energy metabolism and adipogenesis.…”

Fatty Acid Synthase Inhibitor Platensimycin Intervenes the Development of Nonalcoholic Fatty Liver Disease in a Mouse Model

“…Thus, the effective dose of PTM needs to be further explored. Alternatively, manipulating the regulatory pathway of FASN under pathological conditions is a promising method for the treatment of NAFLD, such as the recent identified FASN-binding sorting nexin 8 [ 34 , 36 ]. The direct inhibition of FASN might trigger chronic on-target safety risks due to the reduced β -oxidation of fatty acids by compromising the activity of PPARα, since FASKOL mice showed lipid accumulation and hypoglycemia with a zero-fat diet or fasting.…”

Impact of NAFLD and its pharmacotherapy on lipid profile and CVD

“…Fatty acid synthase catalyzes hepatic DNL and is a key enzyme regulating hepatic lipid metabolism [119]. Studies have demonstrated that FASN expression is significantly elevated in the liver of NAFLD or obesity [120,121].…”

“…Studies have demonstrated that FASN expression is significantly elevated in the liver of NAFLD or obesity [120,121]. Inhibition of FASN improved hepatic steatosis by inhibiting hepatic fatty acid synthesis [119,122,123]. TVB-2640 is a reversible FASN inhibitor that has been shown to reduce hepatic DNL and hepatic TG levels in subjects in a small clinical study.…”