Fatty Liver Due to Increased de novo Lipogenesis: Alterations in the Hepatic Peroxisomal Proteome

Abstract

In non-alcoholic fatty liver disease (NAFLD) caused by ectopic lipid accumulation, lipotoxicity is a crucial molecular risk factor. Mechanisms to eliminate lipid overflow can prevent the liver from functional complications. This may involve increased secretion of lipids or metabolic adaptation to ß-oxidation in lipid-degrading organelles such as mitochondria and peroxisomes. In addition to dietary factors, increased plasma fatty acid levels may be due to increased triglyceride synthesis, lipolysis, as well as de novo lipid synthesis (DNL) in the liver. In the present study, we investigated the impact of fatty liver caused by elevated DNL, in a transgenic mouse model with liver-specific overexpression of human sterol regulatory element-binding protein-1c (alb-SREBP-1c), on hepatic gene expression, on plasma lipids and especially on the proteome of peroxisomes by omics analyses, and we interpreted the results with knowledge-based analyses. In summary, the increased hepatic DNL is accompanied by marginal gene expression changes but massive changes in peroxisomal proteome. Furthermore, plasma phosphatidylcholine (PC) as well as lysoPC species were altered. Based on these observations, it can be speculated that the plasticity of organelles and their functionality may be directly affected by lipid overflow.

Liver Pyruvate Kinase Promotes NAFLD/NASH in Both Mice and Humans in a Sex-Specific Manner

“… 39 Indeed, inhibiting mitochondrial pyruvate import 40 , 41 or mitochondrial citrate export 42 has been shown to reduce DNL and/or revert NAFLD/NASH. In addition, several investigators have shown that increased DNL is a hallmark of NAFLD in both mouse 43 , 44 and human studies. 45 , 46 , 47 Taken together, we believe L-PK–mediated regulation of pyruvate oxidation and DNL is causal in developing steatosis and eventually fibrosis, and limiting this could have a therapeutic potential against NAFLD.…”

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

“…Several peroxisomal oxidases generate hydrogen peroxide during the oxidative activities in the peroxisomes [42][43][44]. NADPH oxidases, the main source of ROS in several liver diseases, generate superoxide anions in the mitochondria by transferring a single electron from NADPH to molecular oxygen [45][46][47].…”

Integrative proteomic and lipidomic analysis of Kaili Sour Soup-mediated attenuation of high-fat diet-induced nonalcoholic fatty liver disease in a rat model

“…Recently, due to the advantages of high-throughput methods, such as genomics, proteomics and lipidomics, systematic analyses of genes, proteins, and metabolites have been utilized to provide more comprehensive information to understand the physiological and pathological processes of various diseases. Several studies have applied proteomic and lipidomic analyses to comprehensively dissect the homeostasis of proteins and lipids in NAFLD [ 9 , 10 ]. However, no studies have focused on global changes in proteins and lipids in NAFLD treated with Kaili Sour Soup.…”