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Alterations of Lipid Profile in Livers with Impaired Lipophagy.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. Various mechanisms such as an increased uptake in fatty acids or de novo synthesis contribute to the development of steatosis and progression to more severe stages. Furthermore, it has been shown that impaired lipophagy, the degradation of lipids by autophagic processes, contributes to NAFLD. Through an unbiased lipidome analysis of mouse livers in a genetic model of impaired lipophagy, we aimed to determine the resulting alterations in the lipidome. Observed changes overlap with those of the human disease. Overall, the entire lipid content and in particular the triacylglycerol concentration increased under conditions of impaired lipophagy. In addition, we detected a reduction in long-chain polyunsaturated fatty acids (PUFAs) and an increased ratio of n-6 PUFAs to n-3 PUFAs, which was due to the depletion of n-3 PUFAs. Although the abundance of major phospholipid classes was reduced, the ratio of phosphatidylcholines to phosphatidylethanolamines was not affected. In conclusion, this study demonstrates that impaired lipophagy contributes to the pathology of NAFLD and is associated with an altered lipid profile. However, the lipid pattern does not appear to be specific for lipophagic alterations, as it resembles mainly that described in relation to fatty liver disease.

SUBMITTER: Jonas W

PROVIDER: S-EPMC9569596 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Alterations of Lipid Profile in Livers with Impaired Lipophagy.

Jonas Wenke W Schwerbel Kristin K Zellner Lisa L Jähnert Markus M Gottmann Pascal P Schürmann Annette A

International journal of molecular sciences 20221006 19

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. Various mechanisms such as an increased uptake in fatty acids or de novo synthesis contribute to the development of steatosis and progression to more severe stages. Furthermore, it has been shown that impaired lipophagy, the degradation of lipids by autophagic processes, contributes to NAFLD. Through an unbiased lipidome analysis of mouse livers in a genetic model of impaired lipophagy, we ai ...[more]

PMID: 36233162

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Project description:Neuroinflammation caused by microglial activation and consequent neurological impairment are prominent features of diabetes-associated cognitive impairment (DACI). Microglial lipophagy, a significant fraction of autophagy contributing to lipid homeostasis and inflammation, had mostly been ignored in DACI. Microglial lipid droplets (LDs) accumulation is a characteristic of aging, however, little is known about the pathological role of microglial lipophagy and LDs in DACI. Therefore, we hypothesized that microglial lipophagy could be an Achilles's heel exploitable to develop effective strategies for DACI therapy. Here, starting with characterization of microglial accumulation of LDs in leptin receptor-deficient (db/db) mice and in high-fat diet and STZ (HFD/STZ) induced T2DM mice, as well as in high-glucose (HG)-treated mice BV2, human HMC3 and primary mice microglia, we revealed that HG-dampened lipophagy was responsible for LDs accumulation in microglia. Mechanistically, accumulated LDs colocalized with the microglial specific inflammatory amplifier TREM1 (triggering receptor expressed on myeloid cells 1), resulting in the buildup of microglial TREM1, which in turn aggravates HG-induced lipophagy damage and subsequently promoted HG-induced neuroinflammatory cascades via NLRP3 (NLR family pyrin domain containing 3) inflammasome. Moreover, pharmacological blockade of TREM1 with LP17 in db/db mice and HFD/STZ mice inhibited accumulation of LDs and TREM1, reduced hippocampal neuronal inflammatory damage, and consequently improved cognitive functions. Taken together, these findings uncover a previously unappreciated mechanism of impaired lipophagy-induced TREM1 accumulation in microglia and neuroinflammation in DACI, suggesting its translational potential as an attractive therapeutic target for delaying diabetes-associated cognitive decline.Abbreviations: ACTB: beta actin; AIF1/IBA1: allograft inflammatory factor 1; ALB: albumin; ARG1: arginase 1; ATG3: autophagy related 3; Baf: bafilomycin A1; BECN1: beclin 1, autophagy related; BW: body weight; CNS: central nervous system; Co-IP: co-immunoprecipitation; DACI: diabetes-associated cognitive impairment; DAPI: 4',6-diamidino-2-phenylindole; DGs: dentate gyrus; DLG4/PSD95: discs large MAGUK scaffold protein 4; DMEM: Dulbecco's modified Eagle's medium; DSST: digit symbol substitution test; EDTA: ethylenedinitrilotetraacetic acid; ELISA: enzyme linked immunosorbent assay; GFAP: glial fibrillary acidic protein; HFD: high-fat diet; HG: high glucose; IFNG/IFN-γ: interferon gamma; IL1B/IL-1β: interleukin 1 beta; IL4: interleukin 4; IL6: interleukin 6; IL10: interleukin 10; LDs: lipid droplets; LPS: lipopolysaccharide; MAP2: microtubule associated protein 2; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MWM: morris water maze; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NLRP3: NLR family pyrin domain containing 3; NOS2/iNOS: nitric oxide synthase 2, inducible; NOR: novel object recognition; OA: oleic acid; PA: palmitic acid; PBS: phosphate-buffered saline; PFA: paraformaldehyde; PLIN2: perilipin 2; PLIN3: perilipin 3; PS: penicillin-streptomycin solution; RAPA: rapamycin; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; RELA/p65: RELA proto-oncogene, NF-kB subunit; ROS: reactive oxygen species; RT: room temperature; RT-qPCR: Reverse transcription quantitative real-time polymerase chain reaction; STZ: streptozotocin; SQSTM1/p62: sequestosome 1; SYK: spleen asociated tyrosine kinase; SYP: synaptophysin; T2DM: type 2 diabetes mellitus; TNF/TNF-α: tumor necrosis factor; TREM1: triggering receptor expressed on myeloid cells 1; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling.

Project description:Uterine fibroids (UF) is the most common (about 70% cases) type of gynecological disease, with the recurrence rate varying from 11 to 40%. Because UF has no distinct symptomatology and is often asymptomatic, the specific and sensitive diagnosis of UF as well as the assessment for the probability of UF recurrence pose considerable challenge. The aim of this study was to characterize alterations in the lipid profile of tissues associated with the first-time diagnosed UF and recurrent uterine fibroids (RUF) and to explore the potential of mass spectrometry (MS) lipidomics analysis of blood plasma samples for the sensitive and specific determination of UF and RUF with low invasiveness of analysis. MS analysis of lipid levels in the myometrium tissues, fibroids tissues and blood plasma samples was carried out on 66 patients, including 35 patients with first-time diagnosed UF and 31 patients with RUF. The control group consisted of 15 patients who underwent surgical treatment for the intrauterine septum. Fibroids and myometrium tissue samples were analyzed using direct MS approach. Blood plasma samples were analyzed using high performance liquid chromatography hyphened with mass spectrometry (HPLC/MS). MS data were processed by discriminant analysis with projection into latent structures (OPLS-DA). Significant differences were found between the first-time UF, RUF and control group in the levels of lipids involved in the metabolism of glycerophospholipids, sphingolipids, lipids with an ether bond, triglycerides and fatty acids. Significant differences between the control group and the groups with UF and RUF were found in the blood plasma levels of cholesterol esters, triacylglycerols, (lyso) phosphatidylcholines and sphingomyelins. Significant differences between the UF and RUF groups were found in the blood plasma levels of cholesterol esters, phosphotidylcholines, sphingomyelins and triacylglycerols. Diagnostic models based on the selected differential lipids using logistic regression showed sensitivity and specificity of 88% and 86% for the diagnosis of first-time UF and 95% and 79% for RUF, accordingly. This study confirms the involvement of lipids in the pathogenesis of uterine fibroids. A diagnostically significant panel of differential lipid species has been identified for the diagnosis of UF and RUF by low-invasive blood plasma analysis. The developed diagnostic models demonstrated high potential for clinical use and further research in this direction.

Dataset Information

Alterations of Lipid Profile in Livers with Impaired Lipophagy.

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Alterations of Lipid Profile in Livers with Impaired Lipophagy.

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