A carbohydrate-restricted diet is a widely recommended intervention for non-alcoholic fatty liver disease (NAFLD), but a systematic perspective on the multiple benefits of this diet is lacking. Here, ...we performed a short-term intervention with an isocaloric low-carbohydrate diet with increased protein content in obese subjects with NAFLD and characterized the resulting alterations in metabolism and the gut microbiota using a multi-omics approach. We observed rapid and dramatic reductions of liver fat and other cardiometabolic risk factors paralleled by (1) marked decreases in hepatic de novo lipogenesis; (2) large increases in serum β-hydroxybutyrate concentrations, reflecting increased mitochondrial β-oxidation; and (3) rapid increases in folate-producing Streptococcus and serum folate concentrations. Liver transcriptomic analysis on biopsy samples from a second cohort revealed downregulation of the fatty acid synthesis pathway and upregulation of folate-mediated one-carbon metabolism and fatty acid oxidation pathways. Our results highlight the potential of exploring diet-microbiota interactions for treating NAFLD.
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•A low-carbohydrate diet (LCD) improves liver fat metabolism in NAFLD patients•The LCD promotes rapid shifts in the gut microbiota composition of NAFLD patients•The LCD-induced microbial changes are associated with increased circulating folate•The LCD increases folate-dependent one-carbon metabolism gene expression in liver
Mardinoglu et al. use multi-omics to investigate the effects of a carbohydrate-restricted diet in obese NAFLD patients. They show that the diet improves liver fat metabolism, promotes rapid shifts in the gut microbiota, increases circulating folate, and upregulates expression of genes involved in folate-dependent one-carbon metabolism in the liver.
To investigate the biological processes that are altered in obese subjects, we generated cell-specific integrated networks (INs) by merging genome-scale metabolic, transcriptional regulatory and ...protein-protein interaction networks. We performed genome-wide transcriptomics analysis to determine the global gene expression changes in the liver and three adipose tissues from obese subjects undergoing bariatric surgery and integrated these data into the cell-specific INs. We found dysregulations in mannose metabolism in obese subjects and validated our predictions by detecting mannose levels in the plasma of the lean and obese subjects. We observed significant correlations between plasma mannose levels, BMI, and insulin resistance (IR). We also measured plasma mannose levels of the subjects in two additional different cohorts and observed that an increased plasma mannose level was associated with IR and insulin secretion. We finally identified mannose as one of the best plasma metabolites in explaining the variance in obesity-independent IR.
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•We generated cell-specific integrated networks for lean and obese subjects•We found dysregulations in the mannose metabolism in obese subjects•Plasma mannose level was associated with insulin resistance independent of BMI•Mannose is used in explaining the variance in obesity-independent insulin resistance
Lee et al. merged genome-scale metabolic models (GEMs), transcriptional regulatory networks (TRNs), and protein-protein interaction networks (PPINs) to generate cell-specific integrated networks for hepatocytes, myocytes, and adipocytes of lean and obese subjects undergoing bariatric surgery. They identified, and independently validated, plasma mannose as highly associated with insulin resistance, independent of BMI.
We performed integrative network analyses to identify targets that can be used for effectively treating liver diseases with minimal side effects. We first generated co‐expression networks (CNs) for ...46 human tissues and liver cancer to explore the functional relationships between genes and examined the overlap between functional and physical interactions. Since increased de novo lipogenesis is a characteristic of nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC), we investigated the liver‐specific genes co‐expressed with fatty acid synthase (FASN). CN analyses predicted that inhibition of these liver‐specific genes decreases FASN expression. Experiments in human cancer cell lines, mouse liver samples, and primary human hepatocytes validated our predictions by demonstrating functional relationships between these liver genes, and showing that their inhibition decreases cell growth and liver fat content. In conclusion, we identified liver‐specific genes linked to NAFLD pathogenesis, such as pyruvate kinase liver and red blood cell (PKLR), or to HCC pathogenesis, such as PKLR, patatin‐like phospholipase domain containing 3 (PNPLA3), and proprotein convertase subtilisin/kexin type 9 (PCSK9), all of which are potential targets for drug development.
Synopsis
Integrative network analyses identify liver‐specific drug targets that can be used to effectively treat liver diseases including nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC).
Co‐expression networks are generated for 46 human tissues and liver cancer.
Genes that are co‐expressed with fatty acid synthase (FASN) only in liver tissue are identified.
Inhibition of liver‐specific genes decreases liver fat and cell growth.
Liver‐specific genes can be targeted in order to treat NAFLD and HCC.
Integrative network analyses identify liver‐specific drug targets that can be used to effectively treat liver diseases including nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC).
New Clues to Human Longevity Piening, Brian D
Clinical chemistry (Baltimore, Md.),
02/2018, Letnik:
64, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Phenotypically, the authors showed that in cultured cells homozygous d3-GHR was associated with lower basal cell proliferation and extracellular-signalregulated kinase (ERK) activation; yet, both ...proliferation and ERK signaling were significantly enhanced upon stimulation with GH, raising the intriguing possibility that a lower threshold for GH stimulation in elderly d3- GHRhomozygotes may provide some protections against metabolic disease, carcinogenesis, or more complex pleiotropies. Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Human Genes: IGF1, insulin-like growth factor 1; GHR, growth hormone receptor.
Radiation therapy induces immunogenic cell death in cancer cells, whereby released endogenous adjuvants are sensed by immune cells to direct adaptive immune responses. TLRs expressed on several ...immune subtypes recognize innate adjuvants to direct downstream inflammatory responses in part via the adapter protein MyD88. We generated Myd88 conditional knockout mice to interrogate its contribution to the immune response to radiation therapy in distinct immune populations in pancreatic cancer. Surprisingly, Myd88 deletion in Itgax (CD11c)-expressing dendritic cells had little discernable effects on response to RT in pancreatic cancer and elicited normal T cell responses using a prime/boost vaccination strategy. Myd88 deletion in Lck-expressing T cells resulted in similar or worsened responses to radiation therapy compared to wild-type mice and lacked antigen-specific CD8
T cell responses from vaccination, similar to observations in Myd88
mice. Lyz2-specific loss of Myd88 in myeloid populations rendered tumors more susceptible to radiation therapy and elicited normal CD8
T cell responses to vaccination. scRNAseq in Lyz2-Cre/Myd88
mice revealed gene signatures in macrophages and monocytes indicative of enhanced type I and II interferon responses, and improved responses to RT were dependent on CD8
T cells and IFNAR1. Together, these data implicate MyD88 signaling in myeloid cells as a critical source of immunosuppression that hinders adaptive immune tumor control following radiation therapy.
Accurate quantitation of antibodies is critical for development of monoclonal antibody therapeutics (mAbs). Therapeutic drug monitoring has been applied to measure levels of mAbs in clinics for dose ...adjustment for autoimmune disease. Trough levels of mAbs can be a biomarker for cancer immunotherapy. Thus, the deployment of a rapid and universal platform for mAb monitoring may benefit processes ranging from drug development to clinical practice for a wide spectrum of diseases. However, mAb monitoring often requires development and conduct of an individual ligand binding assay such as ELISA, which is impractical to scale. We streamlined quantitation of antibody therapeutics by a nano-surface and molecular-orientation limited (nSMOL) proteolysis assay using LC-MS with a universal reference antibody (refmAb-Q), for accurate multiplexed quantitation of unique signature peptides derived from mAbs. This innovative refmAb-Q nSMOL platform may provide a practical solution for quantitating an ever-increasing number of mAbs from developmental to clinical use settings.
Accurate multiplexed quantitation of unique signature peptides derived from monoclonal antibody therapeutics with a universal reference antibody refmAb-Q using Fab-selective proteolysis nSMOL coupled with LC-MS/MS.
Many studies have demonstrated that biological age (BA) varies significantly among individuals of similar chronological age. A recent study by Ahadi et al. used longitudinal and deep multi-omic ...profiling to identify individuals with distinct BA phenotypes or 'ageotypes'. These ageotypes open new avenues to creating diagnostic and treatment strategies that may slow the aging process based on the unique biochemistry of each individual.
T cells recirculate through tissues and lymphatic organs to scan for their cognate antigen. Radiation therapy provides site-specific cytotoxicity to kill cancer cells but also has the potential to ...eliminate the tumor-specific T cells in field. To dynamically study the effect of radiation on CD8 T cell recirculation, we used the Kaede mouse model to photoconvert tumor-infiltrating cells and monitor their movement out of the field of radiation. We demonstrate that radiation results in loss of CD8 T cell recirculation from the tumor to the lymph node and to distant sites. Using scRNASeq, we see decreased proliferating CD8 T cells in the tumor following radiation therapy resulting in a proportional enrichment in exhausted phenotypes. By contrast, 5 days following radiation increased recirculation of T cells from the tumor to the tumor draining lymph node corresponds with increased immunosurveillance of the treated tumor. These data demonstrate that tumor radiation therapy transiently impairs systemic T cell recirculation from the treatment site to the draining lymph node and distant untreated tumors. This may inform timing therapies to improve systemic T cell-mediated tumor immunity.
Purpose
The progression of ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) in humans is highly variable. To better understand the relationship between them, we performed a ...multi-omic characterization of co-occurring DCIS and IBC lesions in a cohort of individuals.
Methods
Formalin-fixed paraffin-embedded tissue samples from 50 patients with co-occurring DCIS and IBC lesions were subjected to DNA-seq and whole transcriptome RNA-seq. Paired DCIS and IBC multi-omics profiles were then interrogated for DNA mutations, gene expression profiles and pathway analysis.
Results
Most small variants and copy number variations were shared between co-occurring DCIS and IBC lesions, with IBC exhibiting on average a higher degree of additional mutations. However, 36% of co-occurring lesions shared no common mutations and 49% shared no common copy number variations. The most frequent genomic variants in both DCIS and IBC were
PIK3CA, TP53, KMT2C, MAP3K1, GATA3
and
SF3B1
, with
KMT2C
being more frequent in DCIS and
TP53
and
MAP3K1
more frequent in IBC, though the numbers are too small for definitive conclusions. The most frequent copy number variations were seen in
MCL1, CKSB1
and
ERBB2. ERBB2
changes were not seen in IBC unless present in the corresponding DCIS. Transcriptional profiles were highly distinct between DCIS and IBC, with DCIS exhibiting upregulation of immune-related signatures, while IBC showed significant overexpression in genes and pathways associated with cell division and proliferation. Interestingly, DCIS and IBC exhibited significant differential expression of different components of extracellular matrix (ECM) formation and regulation, with DCIS showing overexpression of ECM-membrane interaction components while IBC showed upregulation of genes associated with fibronectin and invadopodia.
Conclusion
While most co-occurring DCIS and IBC were mutationally similar and suggestive of a common clonal progenitor, transcriptionally the lesions are highly distinct, with IBC expressing key pathways that facilitate invasion and proliferation. These results are suggestive of additional levels of regulation, epigenetic or other, that facilitate the acquisition of invasive properties during tumor evolution.
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