Nuclear envelope-localized torsinA-LAP1 complex regulates hepatic VLDL secretion and steatosis.

Deciphering novel pathways regulating liver lipid content has profound implications for understanding the pathophysiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Recent evidence suggests that the nuclear envelope is a site of regulation of lipid metabolism but there is limited appreciation of the responsible mechanisms and molecular components within this organelle. We showed that conditional hepatocyte deletion of the inner nuclear membrane protein lamina-associated polypeptide 1 (LAP1) caused defective VLDL secretion and steatosis, including intranuclear lipid accumulation. LAP1 binds to and activates torsinA, an AAA+ ATPase that resides in the perinuclear space and continuous main ER. Deletion of torsinA from mouse hepatocytes caused even greater reductions in VLDL secretion and profound steatosis. Both of these mutant mouse lines developed hepatic steatosis and subsequent steatohepatitis on a regular chow diet in the absence of whole-body insulin resistance or obesity. Our results establish an essential role for the nuclear envelope-localized torsinA-LAP1 complex in hepatic VLDL secretion and suggest that the torsinA pathway participates in the pathophysiology of nonalcoholic fatty liver disease.

Inhibition of apolipoprotein B synthesis stimulates endoplasmic reticulum autophagy that prevents steatosis.

Inhibition of VLDL secretion reduces plasma levels of atherogenic apolipoprotein B (apoB) lipoproteins but can also cause hepatic steatosis. Approaches targeting apoB synthesis, which lies upstream of VLDL secretion, have potential to effectively reduce dyslipidemia but can also lead to hepatic accumulation of unsecreted triglycerides (TG). Here, we found that treating mice with apoB antisense oligonucleotides (ASOs) for 6 weeks decreased VLDL secretion and plasma cholesterol without causing steatosis. The absence of steatosis was linked to an increase in ER stress in the first 3 weeks of ASO treatment, followed by development of ER autophagy at the end of 6 weeks of treatment. The latter resulted in increased fatty acid (FA) oxidation that was inhibited by both chloroquine and 3-methyl adenine, consistent with trafficking of ER TG through the autophagic pathway before oxidation. These findings support the concept that inhibition of apoB synthesis traps lipids that have been transferred to the ER by microsomal TG transfer protein (MTP), inducing ER stress. ER stress then triggers ER autophagy and subsequent lysosomal lipolysis of TG, followed by mitochondrial oxidation of released FA, leading to prevention of steatosis. The identification of this pathway indicates that inhibition of VLDL secretion remains a viable target for therapies aiming to reduce circulating levels of atherogenic apoB lipoproteins.

Behavioral predispositions to approach or avoid emotional words in schizophrenia.

Many data suggest a disjunction between decreased emotional expressions and relatively preserved experience of and ability to assess emotions in schizophrenia. Based in an embodied approach of cognition, several studies have highlighted affective stimulus-response congruency effect in healthy subjects that show a direct link between the perception of emotion and associated motor responses. This study investigated whether the categorization of emotional words involves an automatic sensorimotor simulation of approach and avoidance behaviors. We asked 28 subjects with schizophrenia and 28 controls to execute arm movements of approach or avoidance to categorize emotional words, according to their valence (positive or negative). Controls were faster to respond to a positive stimulus with a movement of approach and a negative stimulus with a movement of avoidance (congruent condition) than to perform the inverted response movements (incongruent condition). However, responses of patients with schizophrenia did not differ according to congruence condition. Our results support the apparent non-involvement of covert sensorimotor simulation of approach and avoidance in the categorization of emotional stimuli by patients with schizophrenia, despite their understanding of the emotional valence of words. This absence of affective stimulus-response compatibility effect would imply a decoupling between emotional and bodily states in patients with schizophrenia.

Clustered hydrophobic amino acids in amphipathic helices mediate erlin1/2 complex assembly.

Erlin1 and erlin2 are highly homologous, ∼40kDa, endoplasmic reticulum membrane proteins that assemble into a ring-shaped complex with a mass of ∼2 MDa. How this complex is formed is not understood, but appears to involve multiple interactions, including a coiled-coil region that mediates lower-order erlin assembly, and a short hydrophobic region, termed the "assembly domain", that mediates higher-order assembly into ∼2 MDa complexes. Here we have used molecular modeling, mutagenesis and cross-linking to examine the role of the assembly domain in higher-order assembly. We find (i) that the assembly domains of erlin1 and erlin2 are amphipathic helices, (ii) that erlin1 alone and erlin2 alone can assemble into ∼2 MDa complexes, (iii) that higher-order assembly is strongly inhibited by point mutations to the assembly domain, (iv) that three interacting hydrophobic residues in the assembly domain and aromaticity are essential for higher-order assembly, and (iv) that while erlins1 and 2 are equally capable of forming lower-order homo- and hetero-oligomers, hetero-oligomers are the most prevalent form when erlin1 and erlin2 are co-expressed. Overall, we conclude that the ∼2 MDa erlin1/2 complex is composed of an assemblage of lower-order hetero-oligomers, probably heterotrimers, linked together by assembly domain hydrophobic residues.

The Prognosis of Survival in Patients with Some Solid Tumors Based on Optimal Partitions of Immunological Parameter Ranges.

New logical and statistical methods were used for the analysis of relationships between survival rate of solid tumor patients and immunological variables. These methods are based on the search of the regularities (syndromes) in the multidimensional space. The syndromes are the elements of partitions of allowable areas of variables. To estimate the statistical validity of found regularities the new technique based on Monte-Carlo computer simulation was used. The broad panel of monoclonal antibodies for lymphocyte differentiation antigens was used for subpopulation analysis. The two tasks are described. The purpose of the first task was the evaluation of significance of immunological parameters for prediction of one-year metastasis-free survival in non-metastatic osteosarcoma of extremities. The second task was the construction of the predicting algorithm for prognosis of two-year survival of patients with stomach cancer. The optimal sets of parameters for prediction of survival were found for both tasks. We found out the high predictive value of HLA DR(+) cells percentage in the 1st task, and the percentage of adhesion cells (CD50(+) lymphocytes) is the most significant parameter in the 2nd task. The predictive algorithms were developed.