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Deciphering novel pathways that regulate liver lipid content has profound implications for understanding the pathophysiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). 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) causes 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. Mice from both of the mutant lines studied 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 NAFLD., Introduction Liver triglyceride (TG) metabolism consists of 3 broad processes. First is the accumulation of fatty acids by hepatocytes from the uptake of plasma fatty acids, the uptake of TG [...]

The study examines the development policy of the circular economy using the example of European Union countries based on the results of their circularity indicators. The respective countries fall into the "shift" country profile according to the distribution from the Global Circularity Gap, being consumers of the majority of global materials and generating 43% of emissions. Through the grouping of EU countries, it was found that high-circularity indicators do not necessarily determine a country's level of environmental friendliness. It has been identified that countries with high resource productivity levels (ranging from 5.8811 to 2.1397%), provided they have high and medium levels of product processing and investment in circular economy development, do not always have a positive impact on the environment. The corresponding research has led to the conclusion that the significant negative impact of the overproduction of goods and excessive resource consumption in European countries, which necessitates appropriate changes in societal activities. There is a need to adjust the policy directions of EU countries to stimulate their sustainable development in a closed-loop economy context, taking into account the specific characteristics and opportunities of each country, which will ensure a more effective adaptation to the implemented innovations. The results of this research can be applied to shaping the circular economy development policy and developing proposals for directions in societal development based on raising awareness about the consequences of interactions with the environment. [ABSTRACT FROM AUTHOR]

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., Introduction Dyslipidemia, the most common atherogenic lipid disorder, is characterized by increased production of VLDL, leading to high plasma levels of triglycerides (TG) and small, dense LDL and reduced concentrations [...]

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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. [ABSTRACT FROM AUTHOR]

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.