Lipidomic biomarkers and mechanisms of lipotoxicity in non-alcoholic fatty liver disease

Svegliati‐Baroni, Gianluca; Pierantonelli, I.; Torquato, Pierangelo; Marinelli, Rita; Ferreri, Carla; Chatgilialoglu, Chryssostomos; Bartolini, Desirée; Galli, Francesco

doi:10.1016/j.freeradbiomed.2019.05.029

Cited by 183 publications

(146 citation statements)

References 207 publications

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“…Furthermore, a marker of lipid peroxidation, e.g., 3-nitrotyrosine, has been found in not only NAFLD patients but also in animal models [207,208]. Peroxidation of mitochondrial membrane components may impair the activity of ETC, ATP depletion, and ROS overproduction [209]. In addition to oxidative damage and ATP depletion, NAFLD development is associated with the induction of cytokines in Kupffer cells and the activation of hepatic stellate cells by contributing to the inflammatory process and favoring the transition of nonalcoholic steatohepatitis to liver fibrosis [141].…”

Section: Hepatic Steatosismentioning

confidence: 99%

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

Rius‐Pérez

Torres-Cuevas

Millán

et al. 2020

Oxidative Medicine and Cellular Longevity

435

292

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Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is a transcriptional coactivator described as a master regulator of mitochondrial biogenesis and function, including oxidative phosphorylation and reactive oxygen species detoxification. PGC-1α is highly expressed in tissues with high energy demands, and it is clearly associated with the pathogenesis of metabolic syndrome and its principal complications including obesity, type 2 diabetes mellitus, cardiovascular disease, and hepatic steatosis. We herein review the molecular pathways regulated by PGC-1α, which connect oxidative stress and mitochondrial metabolism with inflammatory response and metabolic syndrome. PGC-1α regulates the expression of mitochondrial antioxidant genes, including manganese superoxide dismutase, catalase, peroxiredoxin 3 and 5, uncoupling protein 2, thioredoxin 2, and thioredoxin reductase and thus prevents oxidative injury and mitochondrial dysfunction. Dysregulation of PGC-1α alters redox homeostasis in cells and exacerbates inflammatory response, which is commonly accompanied by metabolic disturbances. During inflammation, low levels of PGC-1α downregulate mitochondrial antioxidant gene expression, induce oxidative stress, and promote nuclear factor kappa B activation. In metabolic syndrome, which is characterized by a chronic low grade of inflammation, PGC-1α dysregulation modifies the metabolic properties of tissues by altering mitochondrial function and promoting reactive oxygen species accumulation. In conclusion, PGC-1α acts as an essential node connecting metabolic regulation, redox control, and inflammatory pathways, and it is an interesting therapeutic target that may have significant benefits for a number of metabolic diseases.

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Section: Hepatic Steatosismentioning

confidence: 99%

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

Rius‐Pérez

Torres-Cuevas

Millán

et al. 2020

Oxidative Medicine and Cellular Longevity

435

292

View full text Add to dashboard Cite

show abstract

“…Oxidative stress plays a fundamental role in the initiation and progression of NAFLD. Clinical studies showed elevated oxidative stress and lipid peroxidation in patients with NAFLD 23,24 . Mitochondria are the most significant source of reactive oxygen species (ROS) in NAFLD, mainly due to increased fatty acid oxidation (FAO) upon FFAs overload 25 .…”

Section: Oxidative Stress and Lipotoxicitymentioning

confidence: 99%

Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver?

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD stages range from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) which can progress to cirrhosis and hepatocellular carcinoma. One of the crucial events clearly involved in NAFLD progression is the lipotoxicity resulting from an excessive fatty acid (FFA) influx to hepatocytes. Hepatic lipotoxicity occurs when the capacity of the hepatocyte to manage and export FFAs as triglycerides (TGs) is overwhelmed. This review provides succinct insights into the molecular mechanisms responsible for lipotoxicity in NAFLD, including ER and oxidative stress, autophagy, lipoapotosis and inflammation. In addition, we highlight the role of CD36/FAT fatty acid translocase in NAFLD pathogenesis. Up-to-date, it is well known that CD36 increases FFA uptake and, in the liver, it drives hepatosteatosis onset and might contribute to its progression to NASH. Clinical studies have reinforced the significance of CD36 by showing increased content in the liver of NAFLD patients. Interestingly, circulating levels of a soluble form of CD36 (sCD36) are abnormally elevated in NAFLD patients and positively correlate with the histological grade of hepatic steatosis. In fact, the induction of CD36 translocation to the plasma membrane of the hepatocytes may be a determining factor in the physiopathology of hepatic steatosis in NAFLD patients. Given all these data, targeting the fatty acid translocase CD36 or some of its functional regulators may be a promising therapeutic approach for the prevention and treatment of NAFLD.

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“…Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to determine the expression of specific mRNAs, as previously described [76,77]. Table S1 shows the primer sequences.…”

Section: Quantitative Real-time Pcr (Qrt-pcr)mentioning

confidence: 99%

“…For the expression of either the mRNAs or the microRNAs, the relative quantification method was applied, while using the average Ct of sno202 as a reference, according to the 2 −∆∆CT method. We analyzed the results from the qRT-PCR assays while using the Pfaffl equation [77]. We calculated Ct = (Ct of the target gene in the WT group − Ct of the target gene in the THOP −/− group)/(Ct of the housekeeping gene in the WT group − Ct of the housekeeping gene in the THOP −/− group).…”

Section: Quantitative Real-time Pcr (Qrt-pcr)mentioning

confidence: 99%

The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity

et al. 2020

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Thimet oligopeptidase (EC 3.4.24.15; EP24.15; THOP1) is a potential therapeutic target, as it plays key biological functions in processing biologically functional peptides. The structural conformation of THOP1 provides a unique restriction regarding substrate size, in that it only hydrolyzes peptides (optimally, those ranging from eight to 12 amino acids) and not proteins. The proteasome activity of hydrolyzing proteins releases a large number of intracellular peptides, providing THOP1 substrates within cells. The present study aimed to investigate the possible function of THOP1 in the development of diet-induced obesity (DIO) and insulin resistance by utilizing a murine model of hyperlipidic DIO with both C57BL6 wild-type (WT) and THOP1 null (THOP1−/−) mice. After 24 weeks of being fed a hyperlipidic diet (HD), THOP1−/− and WT mice ingested similar chow and calories; however, the THOP1−/− mice gained 75% less body weight and showed neither insulin resistance nor non-alcoholic fatty liver steatosis when compared to WT mice. THOP1−/− mice had increased adrenergic-stimulated adipose tissue lipolysis as well as a balanced level of expression of genes and microRNAs associated with energy metabolism, adipogenesis, or inflammation. Altogether, these differences converge to a healthy phenotype of THOP1−/− fed a HD. The molecular mechanism that links THOP1 to energy metabolism is suggested herein to involve intracellular peptides, of which the relative levels were identified to change in the adipose tissue of WT and THOP1−/− mice. Intracellular peptides were observed by molecular modeling to interact with both pre-miR-143 and pre-miR-222, suggesting a possible novel regulatory mechanism for gene expression. Therefore, we successfully demonstrated the previously anticipated relevance of THOP1 in energy metabolism regulation. It was suggested that intracellular peptides were responsible for mediating the phenotypic differences that are described herein by a yet unknown mechanism of action.

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Lipidomic biomarkers and mechanisms of lipotoxicity in non-alcoholic fatty liver disease

Cited by 183 publications

References 207 publications

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver?

The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity

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