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Background & Aims Sestrin 1/2/3 (Sesn1/2/3) belong to a small family of proteins that have been implicated in the regulation of metabolic homeostasis and oxidative stress. However, the underlying mechanisms remain incompletely understood. The aim of this work was to illustrate the collective function of Sesn1/2/3 in the protection against hepatic lipotoxicity. Methods We used Sesn1/2/3 triple knockout (TKO) mouse and cell models to characterize oxidative stress and signal transduction under lipotoxic conditions. Biochemical, histologic, and physiological approaches were applied to illustrate the related processes. Results After feeding with a Western diet for 8 weeks, TKO mice developed remarkable metabolic associated fatty liver disease that was manifested by exacerbated hepatic steatosis, inflammation, and fibrosis compared with wild-type counterparts. Moreover, TKO mice exhibited higher levels of hepatic lipotoxicity and oxidative stress. Our biochemical data revealed a critical signaling node from sestrins to c-Jun N-terminal kinases (JNKs) in that sestrins interact with JNKs and mitogen-activated protein kinase kinase 7 and suppress the JNK phosphorylation and activity. In doing so, sestrins markedly reduced palmitate-induced lipotoxicity and oxidative stress in both mouse and human hepatocytes. Conclusions The data from this study suggest that Sesn1/2/3 play an important role in the protection against lipotoxicity-associated oxidative stress and related pathology in the liver., Graphical abstract

Background & Aims Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that is manifested clinically by an increase in hepatic triglycerides, inflammation, and fibrosis. The pathogenesis of NASH remains incompletely understood. Sirtuin 6 (Sirt6), a nicotinamide adenine dinucleotide–dependent deacetylase, has been implicated in fatty liver disease; however, the underlying molecular mechanisms in the NASH pathogenesis are elusive. The aims of this study were to elucidate the role of hepatic Sirt6 in NASH. Methods Wild-type, liver-specific Sirt6 knockout (KO), hepatic stellate cell (HSC)-specific Sirt6 knockout (HSC-KO), and Sirt6 transgenic mice were subjected to a Western diet for 4 weeks. Hepatic phenotypes were characterized and underlying mechanisms were investigated. Results Remarkably, both the liver-KO and HSC-KO mice developed much worse NASH than the wild-type mice, whereas the transgenic mice were protected from the diet-induced NASH. Our cell signaling analysis showed that Sirt6 negatively regulates the transforming growth factor β–Smad family member 3 (Smad3) pathway. Biochemical analysis showed a physical interaction between Sirt6 and Smad3 in hepatic stellate cells. Moreover, our molecular data further showed that Sirt6 deacetylated Smad3 at key lysine residues K333 and K378, and attenuated its transcriptional activity induced by transforming growth factor β in hepatic stellate cells. Conclusions Our data suggest that SIRT6 plays a critical role in the protection against NASH development and it may serve as a potential therapeutic target for NASH., Graphical abstract

Visual Abstract, Highlights • The GLP-1RAs liraglutide and semaglutide reduce cardiovascular risk in type 2 diabetes patients. • In ApoE−/− mice and LDLr−/− mice, liraglutide and semaglutide treatment significantly attenuated plaque lesion development, in part independently of body weight and cholesterol lowering. • Semaglutide decreased levels of plasma markers of systemic inflammation in an acute inflammation model (lipopolysaccharide), and transcriptomic analysis of aortic atherosclerotic tissue revealed that multiple inflammatory pathways were down-regulated by semaglutide., Summary The glucagon-like peptide-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide reduce cardiovascular risk in type 2 diabetes patients. The mode of action is suggested to occur through modified atherosclerotic progression. In this study, both of the compounds significantly attenuated plaque lesion development in apolipoprotein E-deficient (ApoE−/−) mice and low-density lipoprotein receptor-deficient (LDLr−/−) mice. This attenuation was partly independent of weight and cholesterol lowering. In aortic tissue, exposure to a Western diet alters expression of genes in pathways relevant to the pathogenesis of atherosclerosis, including leukocyte recruitment, leukocyte rolling, adhesion/extravasation, cholesterol metabolism, lipid-mediated signaling, extracellular matrix protein turnover, and plaque hemorrhage. Treatment with semaglutide significantly reversed these changes. These data suggest GLP-1RAs affect atherosclerosis through an anti-inflammatory mechanism.

Objective In this study, we analyzed the fatty acid profile of brains and plasma from male and female mice fed chow or a western-style high fat diet (WD) for 16 weeks to determine if males and females process fatty acids differently. Based on the differences in fatty acids observed in vivo, we performed in vitro experiments on N43 hypothalamic neuronal cells to begin to elucidate how the fatty acid milieu may impact brain inflammation. Methods Using a comprehensive mass spectrometry fatty acid analysis, which includes a profile for 52 different fatty acid isomers, we assayed the plasma and brain fatty acid composition of age-matched male and female mice maintained on chow or a WD. Additionally, using the same techniques, we determined the fatty acid composition of N43 hypothalamic cells following exposure to palmitic and linoleic acid, alone or in combination. Results Our data demonstrate there is a sexual dimorphism in brain fatty acid content both following the consumption of the chow diet, as well as the WD, with males having an increased percentage of saturated fatty acids and reductions in ω6-polyunsaturated fatty acids when compared to females. Interestingly, we did not observe a sexual dimorphism in fatty acid content in the plasma of the same mice. Furthermore, exposure of N43 cells to the ω6-PUFA linoleic acid, which is higher in female brains when compared to males, reduces palmitic acid-induced inflammation. Conclusions Our data suggest male and female brains, and not plasma, differ in their fatty acid profile. This is the first time, to our knowledge, lipidomic analyses has been used to directly test the hypothesis there is a sexual dimorphism in brain and plasma fatty acid composition following consumption of the chow diet, as well as following exposure to the WD., Highlights • There is a sexual dimorphism in brain lipid composition. • Brains of male mice following high fat diet exposure are enriched in saturated fatty acids. • Male brains are depleted of polyunsaturated fatty acids following high fat diet exposure. • Linoleic acid inhibits palmitic acid-induced inflammation in hypothalamic cells.