Obesity-Dependent Adipokine Chemerin Suppresses Fatty Acid Oxidation to Confer Ferroptosis Resistance.

Clear cell renal cell carcinoma (ccRCC) is characterized by accumulation of neutral lipids and adipogenic transdifferentiation. We assessed adipokine expression in ccRCC and found that tumor tissues and patient plasma exhibit obesity-dependent elevations of the adipokine chemerin. Attenuation of chemerin by several approaches led to significant reduction in lipid deposition and impairment of tumor cell growth in vitro and in vivo. A multi-omics approach revealed that chemerin suppresses fatty acid oxidation, preventing ferroptosis, and maintains fatty acid levels that activate hypoxia-inducible factor 2α expression. The lipid coenzyme Q and mitochondrial complex IV, whose biogeneses are lipid-dependent, were found to be decreased after chemerin inhibition, contributing to lipid reactive oxygen species production. Monoclonal antibody targeting chemerin led to reduced lipid storage and diminished tumor growth, demonstrating translational potential of chemerin inhibition. Collectively, the results suggest that obesity and tumor cells contribute to ccRCC through the expression of chemerin, which is indispensable in ccRCC biology. SIGNIFICANCE: Identification of a hypoxia-inducible factor-dependent adipokine that prevents fatty acid oxidation and causes escape from ferroptosis highlights a critical metabolic dependency unique in the clear cell subtype of kidney cancer. Targeting lipid metabolism via inhibition of a soluble factor is a promising pharmacologic approach to expand therapeutic strategies for patients with ccRCC.See related commentary by Reznik et al., p. 1879.This article is highlighted in the In This Issue feature, p. 1861.

MBOAT7-driven phosphatidylinositol remodeling promotes the progression of clear cell renal carcinoma.

OBJECTIVE: The most common kidney cancer, clear cell renal cell carcinoma (ccRCC), is closely associated with obesity. The "clear cell" variant of RCC gets its name from the large lipid droplets that accumulate in the tumor cells. Although renal lipid metabolism is altered in ccRCC, the mechanisms and lipids driving this are not well understood. METHODS: We used shotgun lipidomics in human ccRCC tumors and matched normal adjacent renal tissue. To assess MBOAT7s gene expression across tumor severity, we examined histologically graded human ccRCC samples. We then utilized genome editing in ccRCC cell lines to understand the role of MBOAT7 in ccRCC progression. RESULTS: We identified a lipid signature for ccRCC that includes an increase in arachidonic acid-enriched phosphatidylinositols (AA-PI). In parallel, we found that ccRCC tumors have increased expression of acyltransferase enzyme membrane bound O-acyltransferase domain containing 7 (MBOAT7) that contributes to AA-PI synthesis. In ccRCC patients, MBOAT7 expression increases with tumor grade, and increased MBOAT7 expression correlates with poor survival. Genetic deletion of MBOAT7 in ccRCC cells decreases proliferation and induces cell cycle arrest, and MBOAT7-/- cells fail to form tumors in vivo. RNAseq of MBOAT7-/- cells identified alterations in cell migration and extracellular matrix organization that were functionally validated in migration assays. CONCLUSIONS: This study highlights the accumulation of AA-PI in ccRCC and demonstrates a novel way to decrease the AA-PI pool in ccRCC by limiting MBOAT7. Our data reveal that metastatic ccRCC is associated with altered AA-PI metabolism and identify MBOAT7 as a novel target in advanced ccRCC.

Risperidone effects on heterochromatin: the role of kinase signaling.

Epigenetic effects of anti-psychotic medications are poorly understood. We have appropriated a model whereby heterochromatin is established through 24- or 48-h lipopolysaccharide (LPS) treatment, and tested the epigenetic effects of risperidone along the adenylyl cyclase/protein kinase A (AC/PKA) pathway in human liposarcoma cells that express the LPS-sensitive Toll-like receptor (TLR)-4. Human SW872 cells were cultured with LPS and mRNA expression levels and epigenetic modifications of dimethylated lysine 9 of histone 2 (H3K9me2), geterochromatin protein 1γ (HP1γ) and phospho-H3S10 at promoters of interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL1ß were measured. Pharmacological manipulation of the AC/PKA pathway was achieved through treatment with a PKA inhibitor (H89), mitogen- and stress-activated kinase 1 (MSK1) inhibitor (SB-747651A) or forskolin. Twenty-four and 48-h LPS treatment establishes heterochromatin at selected promoters, corresponding to decreased mRNA expression. Concurrent risperidone treatment with LPS treatment can both 'block' and 'reverse' heterochromatin formation. Forskolin treatment resulted in a similar disassembling effect on heterochromatin. Conversely, inhibition of PKA by H89 or MSK1 both blocked 'normalizing' effects of risperidone on LPS-induced heterochromatin. Our results demonstrate that risperidone can disassemble heterochromatin, exerting this effect along the G-protein/AC/PKA pathway. This approach can also be utilized to investigate functional outcomes of single or combined pharmacological treatments on chromatin assemblies in human cells.

Self, Voices and Embodiment: A Phenomenological Analysis.

OBJECTIVE: The primary aim of this study was to examine first-person phenomenological descriptions of the relationship between the self and Auditory Verbal Hallucinations (AVHs). Complex AVHs are frequently described as entities with clear interpersonal characteristics. Strikingly, investigations of first-person (subjective) descriptions of the phenomenology of the relationship are virtually absent from the literature. METHOD: Twenty participants with psychosis and actively experiencing AVHs were recruited from the University of Illinois at Chicago. A mixed-methods design involving qualitative and quantitative components was utilized. Following a priority-sequence model of complementarity, quantitative analyses were used to test elements of emergent qualitative themes. RESULTS: The qualitative analysis identified three foundational constructs in the relationship between self and voices: 'understanding of origin,' 'distinct interpersonal identities,' and 'locus of control.' Quantitative analyses further supported identified links of these constructs. Subjects experienced their AVHs as having identities distinct from self and actively engaged with their AVHs experienced a greater sense of autonomy and control over AVHs. DISCUSSION: Given the clinical importance of AVHs and emerging strategies targeting the relationship between the hearer and voices, our findings highlight the importance of these relational constructs in improvement and innovation of clinical interventions. Our analyses also underscore the value of detailed voice assessments such as those provided by the Maastricht Interview are needed in the evaluation process. Subjects narratives shows that the relational phenomena between hearer and AVH(s) is dynamic, and can be influenced and changed through the hearers' engagement, conversation, and negotiation with their voices.

Heterochromatin as an incubator for pathology and treatment non-response: implication for neuropsychiatric illness.

Heterochromatin is a higher order assembly that is characterized by a genome-wide distribution, gene-repression, durability and potential to spread. In this light, it is an appealing mechanism to interpret the neurobiology of complex brain disorders such as schizophrenia where downregulation of expression appears to be the norm. H3K9 methylation (H3K9me) can initiate the seeding of a heterochromatin assembly on an inactive or poorly coordinated promoter as a consequence of a decline in transactivators either from disuse or from misuse. H3K9me can extend its influence by spatial spreading through the mechanism of recursively recruiting adapters, such as heterochromatin protein 1 (HP1) homodimers. HP1 itself serves as a platform for other repressive proteins such as DNA methyltransferases. In full color, heterochromatin can occupy genome-wide gene networks, tissue specific ontologies and even rearrange the nuclear architecture. Heterochromatin in the brain is modified by small molecule pharmacology and serves a physiological role in the functioning of dopamine neurons and the construction of memory. From a therapeutic perspective, the durable nature of heterochromatin implies that it may require disassembly before the full genomic-potential of standard pharmacotherapies is achieved, especially in treatment resistant patients.

Categorizing partner-violent men within the reactive-proactive typology model.

A system for categorizing partner-violent men as either reactive or proactive aggressors was developed and evaluated in the present study. Sixty partner-violent men were reliably categorized, and the distribution (62% reactive, 38% proactive) fell within the expected range. Some construct validity was demonstrated, as several significant predicted group differences were found on factors of theoretical relevance to the typology model (affectivity, personality, and violence in the family-of-origin). Proactively versus reactively categorized participants were (a) more dominant and less angry during a 10-min interpartner interaction, (b) more antisocial and aggressive-sadistic and less dependent, and (c) more frequently classified as psychopathic (17% vs. 0%). Research and clinical implications of the system are discussed, as is the potential overlap between the reactively and proactively categorized partner-violent men in this study with previously identified types.

Specificity of dating aggression and its justification among high-risk adolescents.

Ninety-five high-risk adolescents were studied to determine whether their dating aggression and its justification as a response to interpersonal problems were specific to the current partner, general to dating relationships, or part of a global age-mate (same-sex peers and opposite-sex dating partners) aggression problem. Approximately one-third of males and two-thirds of females reported physical aggression against their current dating partner. Males' aggression (and its justification) toward their current dating partner was part of a generalized pattern of dating aggression, whereas for females, physical aggression against a current dating partner (and its justification) was partner-specific and unrelated to aggression in other relationships. Findings are discussed with regard to intervention and future research on adolescent dating aggression.

Comparison of figural intrusion errors in three amnesic subgroups.

To examine the contribution of memory deficits and executive dysfunction to the production of prior-item intrusion errors, Korsakoff, mesial temporal amnesic, and anterior communicating artery aneurysm (ACoA) patients' performance on the Visual Reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R) was assessed. The Korsakoff patients were matched to the mesial temporal group in terms of severity of amnesia, while the ACoA group, which was less severely amnesic, was matched to the Korsakoff group in their performance on executive tests. Results indicated that at immediate recall, Korsakoff patients made significantly more intrusions than mesial temporal and ACoA patients. Conversely, after a delay, ACoA patients tended to make more intrusions than the other groups. Findings suggest that intrusions are due to a combination of deficient memory and executive dysfunction. A further comparison of a subgroup of ACoA patients matched to the Korsakoff patients in terms of severity of amnesia, however, revealed differences in the pattern of intrusions of these two groups, suggesting that different mechanisms may underlie Korsakoff and ACoA patients' susceptibility to interference.