Impaired hepatic autophagy exacerbates hepatotoxin induced liver injury.

Hepatotoxins activate the hepatic survival pathway, but it is unclear whether impaired survival pathways contribute to liver injury caused by hepatotoxins. We investigated the role of hepatic autophagy, a cellular survival pathway, in cholestatic liver injury driven by a hepatotoxin. Here we demonstrate that hepatotoxin contained DDC diet impaired autophagic flux, resulting in the accumulation of p62-Ub-intrahyaline bodies (IHBs) but not the Mallory Denk-Bodies (MDBs). An impaired autophagic flux was associated with a deregulated hepatic protein-chaperonin system and significant decline in Rab family proteins. Additionally, p62-Ub-IHB accumulation activated the NRF2 pathway rather than the proteostasis-related ER stress signaling pathway and suppressed the FXR nuclear receptor. Moreover, we demonstrate that heterozygous deletion of Atg7, a key autophagy gene, aggravated the IHB accumulation and cholestatic liver injury. Conclusion: Impaired autophagy exacerbates hepatotoxin-induced cholestatic liver injury. The promotion of autophagy may represent a new therapeutic approach for hepatotoxin-induced liver damage.

Therapeutic regulation of autophagy in hepatic metabolism.

Metabolic homeostasis requires dynamic catabolic and anabolic processes. Autophagy, an intracellular lysosomal degradative pathway, can rewire cellular metabolism linking catabolic to anabolic processes and thus sustain homeostasis. This is especially relevant in the liver, a key metabolic organ that governs body energy metabolism. Autophagy's role in hepatic energy regulation has just begun to emerge and autophagy seems to have a much broader impact than what has been appreciated in the field. Though classically known for selective or bulk degradation of cellular components or energy-dense macromolecules, emerging evidence indicates autophagy selectively regulates various signaling proteins to directly impact the expression levels of metabolic enzymes or their upstream regulators. Hence, we review three specific mechanisms by which autophagy can regulate metabolism: A) nutrient regeneration, B) quality control of organelles, and C) signaling protein regulation. The plasticity of the autophagic function is unraveling a new therapeutic approach. Thus, we will also discuss the potential translation of promising preclinical data on autophagy modulation into therapeutic strategies that can be used in the clinic to treat common metabolic disorders.

Assessing interpersonal aspects of schizoid personality disorder: preliminary validation studies.

In 2 studies, we examined the reliability and validity of an interpersonal measure of schizoid personality disorder (SZPD) based on nonverbal behaviors and interpersonal interactions occurring during interviews. A total of 556 male jail inmates in the United States participated in Study 1; 175 mentally disordered offenders in maximum security hospitals in the United Kingdom participated in Study 2. Across both samples, scores on the Interpersonal Measure of Schizoid Personality Disorder (IM-SZ) exhibited adequate reliability and patterns of correlations with other measures consistent with expectations. The scale displayed patterns of relatively specific correlations with interview and self-report measures of SZPD. In addition, the IM-SZ correlated in an expected manner with features of psychopathy and antisocial personality and with independent ratings of interpersonal behavior. We address implications for assessment of personality disorder.

Testing neuropsychological hypotheses for cognitive deficits in psychopathic criminals: a study of global-local processing.

Competing hypotheses about neuropsychological mechanisms underlying psychopathy are seldom examined in the same study. We tested the left hemisphere activation hypothesis and the response modulation hypothesis of psychopathy in 172 inmates completing a global-local processing task under local bias, global bias, and neutral conditions. Consistent with the left hemisphere activation hypothesis, planned comparisons showed that psychopathic inmates classified local targets more slowly than nonpsychopathic inmates in a local bias condition and exhibited a trend toward similar deficits for global targets in this condition. However, contrary to the response modulation hypothesis, psychopaths were no slower to respond to local targets in a global bias condition. Because psychopathic inmates were not generally slower to respond to local targets, results are also not consistent with a general left hemisphere dysfunction account. Correlational analyses also indicated deficits specific to conditions presenting most targets at the local level initially. Implications for neuropsychological conceptualizations of psychopathy are considered.