| 1. |
- Benfeitas, Rui, et al.
(författare)
-
Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysis
- 2019
-
Ingår i: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 40, s. 471-487
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Redox metabolism is often considered a potential target for cancer treatment, but a systematic examination of redox responses in hepatocellular carcinoma (HCC) is missing. Methods: Here, we employed systems biology and biological network analyses to reveal key roles of genes associated with redox metabolism in HCC by integrating multi-omics data. Findings: We found that several redox genes, including 25 novel potential prognostic genes, are significantly co-expressed with liver-specific genes and genes associated with immunity and inflammation. Based on an integrative analysis, we found that HCC tumors display antagonistic behaviors in redox responses. The two HCC groups are associated with altered fatty acid, amino acid, drug and hormone metabolism, differentiation, proliferation, and NADPH-independent vs - dependent antioxidant defenses. Redox behavior varies with known tumor subtypes and progression, affecting patient survival. These antagonistic responses are also displayed at the protein and metabolite level and were validated in several independent cohorts. We finally showed the differential redox behavior using mice transcriptomics in HCC and noncancerous tissues and associated with hypoxic features of the two redox gene groups. Interpretation: Our integrative approaches highlighted mechanistic differences among tumors and allowed the identification of a survival signature and several potential therapeutic targets for the treatment of HCC.
|
|
| 2. |
- Klevstig, Martina, et al.
(författare)
-
Cardiac expression of the microsomal triglyceride transport protein protects the heart function during ischemia
- 2019
-
Ingår i: Journal of Molecular and Cellular Cardiology. - : Elsevier BV. - 0022-2828 .- 1095-8584. ; 137, s. 1-8
-
Tidskriftsartikel (refereegranskat)abstract
- Aims: The microsomal triglyceride transport protein (MTTP) is critical for assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins and is most abundant in the liver and intestine. Surprisingly, MTTP is also expressed in the heart. Here we tested the functional relevance of cardiac MTTP expression. Materials and methods: We combined clinical studies, advanced expression analysis of human heart biopsies and analyses in genetically modified mice lacking cardiac expression of the MTTP-A isoform of MTTP. Results: Our results indicate that lower cardiac MTTP expression in humans is associated with structural and perfusion abnormalities in patients with ischemic heart disease. MTTP-A deficiency in mice heart does not affect total MTTP expression, activity or lipid concentration in the heart. Despite this, MTTP-A deficient mice displayed impaired cardiac function after a myocardial infarction. Expression analysis of MTTP indicates that MTTP expression is linked to cardiac function and responses in the heart. Conclusions: Our results indicate that MTTP may play an important role for the heart function in conjunction to ischemic events.
|
|
| 3. |
- Liu, Zhengtao, et al.
(författare)
-
Pyruvate kinase L/R is a regulator of lipid metabolism and mitochondrial function
- 2019
-
Ingår i: Metabolic Engineering. - : Elsevier BV. - 1096-7176 .- 1096-7184. ; 52, s. 263-272
-
Tidskriftsartikel (refereegranskat)abstract
- The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) has been associated with altered expression of liver-specific genes including pyruvate kinase liver and red blood cell (PKLR), patatin-like phospholipase domain containing 3 (PNPLA3) and proprotein convertase subtilisin/kexin type 9 (PCSK9). Here, we inhibited and overexpressed the expression of these three genes in HepG2 cells, generated RNA-seq data before and after perturbation and revealed the altered global biological functions with the modulation of these genes using integrated network (IN) analysis. We found that modulation of these genes effects the total triglycerides levels within the cells and viability of the cells. Next, we generated IN for HepG2 cells, identified reporter transcription factors based on IN and found that the modulation of these genes affects key metabolic pathways associated with lipid metabolism (steroid biosynthesis, PPAR signalling pathway, fatty acid synthesis and oxidation) and cancer development (DNA replication, cell cycle and p53 signalling) involved in the progression of NAFLD and HCC. Finally, we observed that inhibition of PKLR lead to decreased glucose uptake and decreased mitochondrial activity in HepG2 cells. Hence, our systems level analysis indicated that PKLR can be targeted for development efficient treatment strategy for NAFLD and HCC.
|
|
| 4. |
- Mardani, Ismena, et al.
(författare)
-
Plin2-deficiency reduces lipophagy and results in increased lipid accumulation in the heart.
- 2019
-
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
-
Tidskriftsartikel (refereegranskat)abstract
- Myocardial dysfunction is commonly associated with accumulation of cardiac lipid droplets (LDs). Perilipin 2 (Plin2) is a LD protein that is involved in LD formation, stability and trafficking events within the cell. Even though Plin2 is highly expressed in the heart, little is known about its role in myocardial lipid storage. A recent report shows that cardiac overexpression of Plin2 result in massive myocardial steatosis suggesting that Plin2 stabilizes LDs. In this study, we hypothesized that deficiency in Plin2 would result in reduced myocardial lipid storage. In contrast to our hypothesis, we found increased accumulation of triglycerides in hearts, and specifically in cardiomyocytes, from Plin2-/- mice. Although Plin2-/- mice had markedly enhanced lipid levels in the heart, they had normal heart function under baseline conditions and under mild stress. However, after an induced myocardial infarction, stroke volume and cardiac output were reduced in Plin2-/- mice compared with Plin2+/+ mice. We further demonstrated that the increased triglyceride accumulation in Plin2-deficient hearts was caused by altered lipophagy. Together, our data show that Plin2 is important for proper hydrolysis of LDs.
|
|
| 5. |
- Sämfors, Sanna, 1987, et al.
(författare)
-
Localised lipid accumulation detected in infarcted mouse heart tissue using ToF-SIMS
- 2019
-
Ingår i: International Journal of Mass Spectrometry. - : Elsevier BV. - 1387-3806. ; 437, s. 77-86
-
Tidskriftsartikel (refereegranskat)abstract
- Cardiovascular disease (CVD) is largely related to complications from atherosclerotic disease such as myocardial infarction (MI) and ischemic stroke and accounts for more than 30% of overall global mortality. Understanding the biochemical changes that occur in cardiac tissue following myocardial infarction is critical for clarifying the mechanisms underlying the impaired heart function seen after a myocardial infarction. Lipids have been shown to accumulate in ischemic cardiac tissue following an infarction. Recent data indicate that this cardiac lipid accumulation induces apoptosis and loss of muscle cells during the post-infarction period, which aggravate the functional impairment in the heart and limit its adaptive capacity for compensatory remodelling. It is therefore important to identify the lipids and molecular mechanisms that induce these destructive responses. In this study, the spatial distribution of lipids in mouse cardiac tissue after surgically induced infarction were identified using ToF-SIMS imaging with a gas cluster ion beam (GCIB). The benefits of frozen hydrated analysis versus freeze dried sample preparation were assessed as was the suitability of different multivariate analysis techniques for identification of localised chemical changes in the tissue. Results show that differences in intensity of the peaks in the mass spectrum corresponding to different lipids can be detected between the infarcted region of the heart and normal tissue region as well as specific accumulation of acyl-carnitine species at the boundary of the damaged region. Different spatial distributions of lipids were detected in both positive and negative ion mode providing insights into the changes in lipid metabolism following infarction. The ToF-SIMS results were compared with conventional lipidomics where although many lipid classes show similar changes between infarcted and non-infarcted hearts the ToF-SIMS data revealed differences due to salt adduct formation and most importantly where the changes in lipid signal are highly localised at the border between the infarcted and non-infarcted regions of the heart. (C) 2017 Elsevier B.V. All rights reserved.
|
|
