Palm Oil-Rich Diet Affects Murine Liver Proteome and S-Palmitoylome

Ziemlińska, Ewelina; Sobocińska, Justyna; Świątkowska, Anna; Hromada-Judycka, Aneta; Traczyk, Gabriela; Malinowska, Agata; Świderska, Bianka; Mietelska‐Porowska, Anna; Ciesielska, Anna; Kwiatkowska, Katarzyna

doi:10.3390/ijms222313094

Cited by 12 publications

(7 citation statements)

References 80 publications

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“…The acyl-biotin exchange technique was applied to detect S -palmitoylation of DGKε essentially as described previously (36), with minor modifications. In brief, HEK293 cells were lysed in 500 μl of 150 mM NaCl, 5 mM EDTA, 1.7% Triton X-100, 4% SDS, cOmplete protease inhibitor cocktail, 2 mM PMSF, 250 U/ml Benzonase Nuclease, 50 mM Tris, pH 7.2, for 15 min at 37°C with shaking, followed by sonication for 60 s (0.3 cycle; amplitude 33%; UP200S Hielscher sonifier).…”

Section: Methodsmentioning

confidence: 99%

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Diacylglycerol kinase-ε isS-palmitoylated on cysteine in the cytoplasmic end of its N-terminal transmembrane fragment

Traczyk

Hromada-Judycka

Swiatkowska

et al. 2023

Preprint

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Diacylglycerol kinase-epsilon (DGKepsilon) catalyzes phosphorylation of diacylglycerol to phosphatidic acid with a unique specificity toward 1-stearoyl-2-arachidonoyl-sn-glycerol which is a backbone of phosphatidylinositol (PI).DGKepsilon plays a crucial role in the PI cycle thereby maintaining the cellular level of phosphorylated PI derivatives of signaling activity, and in lipid metabolism. DGKepsilon dysfunction is linked with the development of atypical hemolytic uremic syndrome (aHUS) and other diseases in humans. Despite the DGKepsilon significance, data on the regulation of its functioning by possible co/post-translational modifications are scarce. Here we report that DGKepsilon is S-palmitoylated at Cys38/40 (mouse/human DGKepsilon) located at the cytoplasmic end of its N-terminal putative transmembrane fragment. The S-palmitoylation of DGKepsilon was revealed by metabolic labeling of cells with a palmitic acid analogue followed by click chemistry, and with acyl-biotin and acyl-PEG exchange assays. The zDHHC7, 17 and 6/16 S-acyltransferases were found to catalyze DGKepsilon S-palmitoylation which also increased the DGKepsilon abundance, likely by affecting its stability. Given the localization of the majority of DGKepsilon and zDHHC6 in the endoplasmic reticulum and zDHHC7 and zDHHC17 in the Golgi apparatus, trafficking of a fraction of DGKepsilon through the Golgi apparatus toward the plasma membrane is plausible. The Cys38Ala substitution moderately upregulated the activity of DGKepsilon, suggesting an inhibitory effect of the acylation in wild type DGKepsilon. In contrast to Cys38Ala, the substitution of neighboring Pro31 with Ala diminished the amount and the activity of DGKepsilon. Taken together, our data indicate that S-palmitoylation can fine-tune DGKepsilon activity and affect its abundance and cellular localization.

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Section: Methodsmentioning

confidence: 99%

Section: Acyl-biotin Exchangementioning

confidence: 99%

Diacylglycerol kinase-ε isS-palmitoylated on cysteine in the cytoplasmic end of its N-terminal transmembrane fragment

Traczyk

Hromada-Judycka

Swiatkowska

et al. 2023

Preprint

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“…Besides using enzyme modulators, dietary palmitate impacts the palmitoylation status of proteins. For instance, a palm oil-rich diet leads to accumulation of palmitate in membrane-enriched fractions of murine livers, as well as altered S-palmitoylation of proteins involved in the metabolism of fatty acids and cholesterol, such as fatty acid synthase, fatty acid elongase 2, stearoyl-CoA desaturase-1, CD36, and lanosterol synthase [122]. Similarly, several studies found that a high-fat diet, mainly enriched in animal fats, alters the S-palmitoylation of numerous proteins in peripheral organs and the central nervous systems, including but not limited to CD36 and the GluA1 subunit of the AMPA receptor [46,[123][124][125].…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Protein Lipidation by Palmitate Controls Macrophage Function

Guns

Vanherle

Hendriks

et al. 2022

Cells

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Macrophages are present in all tissues within our body, where they promote tissue homeostasis by responding to microenvironmental triggers, not only through clearance of pathogens and apoptotic cells but also via trophic, regulatory, and repair functions. To accomplish these divergent functions, tremendous dynamic fine-tuning of their physiology is needed. Emerging evidence indicates that S-palmitoylation, a reversible post-translational modification that involves the linkage of the saturated fatty acid palmitate to protein cysteine residues, directs many aspects of macrophage physiology in health and disease. By controlling protein activity, stability, trafficking, and protein–protein interactions, studies identified a key role of S-palmitoylation in endocytosis, inflammatory signaling, chemotaxis, and lysosomal function. Here, we provide an in-depth overview of the impact of S-palmitoylation on these cellular processes in macrophages in health and disease. Findings discussed in this review highlight the therapeutic potential of modulators of S-palmitoylation in immunopathologies, ranging from infectious and chronic inflammatory disorders to metabolic conditions.

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“…The proteins involved in promoting various PTMs exist in several subcellular organelles, including the cytoplasm [ 39 ], ER [ 40 , 41 ], mitochondria [ 42 ], and nucleus [ 43 ]; PTMs may also be observed in the proteomes of the liver [ 37 , 44 – 47 ], gut [ 7 ], and other peripheral tissues [ 29 ]. PTMs found in liver diseases include protein acetylation [ 37 , 42 , 48 ], nitration [ 10 , 26 , 37 , 49 – 53 ], S -nitrosylation [ 49 , 54 , 55 ], oxidation [ 37 ], phosphorylation [ 26 , 56 , 57 ], succinylation [ 58 ], ADP-ribosylation [ 44 ], ubiquitination [ 37 , 59 ], SUMOylation [ 60 – 65 ], carbonylation [ 66 – 68 ], S -palmitoylation [ 45 – 47 , 69 ], glycosylation [ 7 , 37 , 70 , 71 ], protein adducts of aldehyde (i.e., acetaldehydes) [ 9 , 72 ], lipid peroxidation products (LPOs), and advanced glycation end products (AGEs) [ 6 , 66 , 74 – 79 ]. Several studies detail that specific PTMs correlate with exposures to excessive alcohol [ 80 , 81 ], CCl 4 [ 7 , 56 ], acetaminophen (APAP) [ 53 , 82 ], 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) [ 39 ], or fructose [ 51 ].…”

Section: Introductionmentioning

confidence: 99%

Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction

LeFort,

Rungratanawanich,

Song

2024

Cell. Mol. Life Sci.

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This review provides an update on recent findings from basic, translational, and clinical studies on the molecular mechanisms of mitochondrial dysfunction and apoptosis of hepatocytes in multiple liver diseases, including but not limited to alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and drug-induced liver injury (DILI). While the ethanol-inducible cytochrome P450-2E1 (CYP2E1) is mainly responsible for oxidizing binge alcohol via the microsomal ethanol oxidizing system, it is also responsible for metabolizing many xenobiotics, including pollutants, chemicals, drugs, and specific diets abundant in n-6 fatty acids, into toxic metabolites in many organs, including the liver, causing pathological insults through organelles such as mitochondria and endoplasmic reticula. Oxidative imbalances (oxidative stress) in mitochondria promote the covalent modifications of lipids, proteins, and nucleic acids through enzymatic and non-enzymatic mechanisms. Excessive changes stimulate various post-translational modifications (PTMs) of mitochondrial proteins, transcription factors, and histones. Increased PTMs of mitochondrial proteins inactivate many enzymes involved in the reduction of oxidative species, fatty acid metabolism, and mitophagy pathways, leading to mitochondrial dysfunction, energy depletion, and apoptosis. Unique from other organelles, mitochondria control many signaling cascades involved in bioenergetics (fat metabolism), inflammation, and apoptosis/necrosis of hepatocytes. When mitochondrial homeostasis is shifted, these pathways become altered or shut down, likely contributing to the death of hepatocytes with activation of inflammation and hepatic stellate cells, causing liver fibrosis and cirrhosis. This review will encapsulate how mitochondrial dysfunction contributes to hepatocyte apoptosis in several types of liver diseases in order to provide recommendations for targeted therapeutics.

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Palm Oil-Rich Diet Affects Murine Liver Proteome and S-Palmitoylome

Cited by 12 publications

References 80 publications

Diacylglycerol kinase-ε isS-palmitoylated on cysteine in the cytoplasmic end of its N-terminal transmembrane fragment

Diacylglycerol kinase-ε isS-palmitoylated on cysteine in the cytoplasmic end of its N-terminal transmembrane fragment

Protein Lipidation by Palmitate Controls Macrophage Function

Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction

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