Sirt3-Sod2-mROS-Mediated Manganese Triggered Hepatic Mitochondrial Dysfunction and Lipotoxicity in a Freshwater Teleost

Abstract

Exposure to excessive manganese (Mn) is toxic to humans and animals. However, the toxic effects and mechanisms of excessive Mn influencing the vertebrates have been highly overlooked. In the present study, dietary Mn overload significantly increased hepatic lipid and Mn contents, decreased superoxide dismutase 2 (Sod2) activity, increased the Sod2 acetylation level, and induced mitochondrial dysfunction; Mn induced mitochondrial dysfunction through Mtf1/sirtuin 3 (Sirt3)-mediated acetylation of Sod2 at the sites K55 and K70. Meanwhile, mitochondrial oxidative stress was involved in Mninduced lipotoxicity. Mechanistically, Mn-induced lipotoxicity was via oxidative stressinduced Hsf1 nucleus translocation and its DNA binding capacity to the regions of a peroxisome proliferator-activated receptor g (pparg) promoter, which in turn induced the transcription of lipogenic-related target genes. For the first time, our study demonstrated that Mn-induced hepatic lipotoxicity via a mitochondrial oxidative stress-dependent Hsf1/Pparg pathway and Mtf1/sirt3-mediated Sod2 acetylation participated in mitochondrial dysfunction. Considering that lipid metabolism and lipotoxicity are widely used as the biomarkers for environmental assessments of pollutants, our study provided innovative and important insights into Mn toxicological and environmental evaluation in aquatic environments.

Phosphorus Overload Promotes Hepatic Lipolysis by Suppressing GSK3β-Dependent Phosphorylation of PPARα at Ser84 and Thr265 in a Freshwater Teleost

“…9 The main function of PPARα is to reduce hepatic steatosis through targeting genes involved in the β-oxidation pathway, including long-chain fatty acid transport protein 1 (fatp1), fatty acid-binding protein 1 (fabp1), carnitine O-palmitoyltransferase 1a (cpt1a), cpt2, long-chain-specific acyl-CoA dehydrogenase (acadl), and enoyl-CoA hydratase (echs). 8,13,18 It has been reported that a carbohydrate-rich diet increases phosphorylation of PPARα at Ser 12, while fasting inhibits PPARα phosphorylation in Nile tilapia. 19,20 Studies also suggested that PPARα activity and functions are controlled by its phosphorylation and that GSK3α and GSK3β are important upstream regulators.…”

“…Lipids constitute crucial components of biological membranes and signaling molecules for many cellular processes . Insufficient lipid mass is detrimental to the growth, reproduction, health, and population size of fish. , Specific types of lipids may be used as biomarkers for environmental monitoring of pollutants since abnormal lipolytic metabolism will adversely influence growth, survival, propagation, migration, and health . The liver is a major organ for lipid deposition and metabolism in vertebrates. , Many research studies demonstrated that the liver is one of the major target organs for pollutants, and hepatic lipid metabolism will change in response to adverse environmental conditions. , Pi overload is common in the aquatic environment. , Studies suggested that Pi overload suppressed hepatic lipogenesis and increased fatty acid oxidation, which affected the growth and health of animals. , However, the risk of Pi overload on teleost fish and the relevant mechanism remain unknown.…”

“…Among them, peroxisome proliferator-activated receptor α (PPARα) is one of the most studied transcriptional factors in fish species exposed to contaminants . The main function of PPARα is to reduce hepatic steatosis through targeting genes involved in the β-oxidation pathway, including long-chain fatty acid transport protein 1 ( fatp1 ), fatty acid-binding protein 1 ( fabp1 ), carnitine O -palmitoyltransferase 1a ( cpt1a ), cpt2 , long-chain-specific acyl-CoA dehydrogenase ( acadl ), and enoyl-CoA hydratase ( echs ). ,, It has been reported that a carbohydrate-rich diet increases phosphorylation of PPARα at Ser 12, while fasting inhibits PPARα phosphorylation in Nile tilapia. , Studies also suggested that PPARα activity and functions are controlled by its phosphorylation and that GSK3α and GSK3β are important upstream regulators. , Thus, considering that PPARα is an important transcriptional factor for regulating the lipolytic mechanism and that GSK3α and GSK3β are critical upstream regulators for PPARα function, we hypothesize that Pi overload induces lipolysis via the PPARα pathway under the control of GSK3.…”

“…Teleost fish are the most abundant species among vertebrates, and extensive research has demonstrated some reactions of fish species to contaminated aquatic environments. , While fish may acquire phosphorus via diet and water, the diet is the primary source for Pi under natural conditions. , The yellow catfish Pelteobagrus fulvidraco, a widely distributed teleost fish in China and other countries, is a suitable model for the environmental risk assessment of pollutants due to its available genomic information and importance in aquatic ecosystems. , Pi is an important element that induces eutrophication in natural waters, ultimately threatening human and fish health. Pi is also involved in the regulation of many biological processes. , Therefore, pollution and toxicity of Pi pose a direct threat to the health of aquatic animals.…”

“…6 Insufficient lipid mass is detrimental to the growth, reproduction, health, and population size of fish. 7,8 Specific types of lipids may be used as biomarkers for environmental monitoring of pollutants since abnormal lipolytic metabolism will adversely influence growth, survival, propagation, migration, and health. 9 The liver is a major organ for lipid deposition and metabolism in vertebrates.…”