Endoplasmic reticulum stress, initiated by protein overload or malfolding, activates a complex network of interacting and parallel responses that dampen the stress. However, when the protective response is insufficient, a set of responses leads to apoptosis. Coupled with the latter are promotion of lipid synthesis and proinflammatory responses. Evidence has been mounting for an important role of the endoplasmic reticulum (ER) stress response in the pathogenesis of chronic viral hepatitis, insulin resistance and nonalcoholic fatty liver disease, ischemia-reperfusion injury, genetic disorders of protein malfolding, and alcoholic liver disease. In the latter, a key candidate for inducing ER stress is hyperhomocysteinemia. Betaine treatment promotes removal of homocysteine and prevents ER stress, fatty liver, and apoptosis in a mouse model of alcohol-induced liver disease. With increasing interest in the potential role of ER stress in liver disease, greater understanding of pathophysiology, prevention, and treatment of liver disease is anticipated.
Deconvolution analysis (DA) based on singular value decomposition (SVD) has been widely accepted for quantification of cerebral blood flow (CBF) using dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSC-MRI). When using this method, the elements in the diagonal matrix obtained by SVD are set to zero when they are smaller than the threshold value given beforehand. In the present study, we investigated the effect of the threshold value on the accuracy of the CBF values obtained by this method using computer simulations. We also investigated the threshold value giving the CBF closest to the assumed value (optimal threshold value) under various conditions. The CBF values obtained by this method largely depended on the threshold value. Both the mean and the standard deviation of the estimated CBF values decreased with increasing threshold value. The optimal threshold value decreased with increasing signal-to-noise ratio and CBF, and increased with increasing cerebral blood volume. Although delay and dispersion in the arterial input function also affected the relationship between the estimated CBF and threshold values, the optimal threshold value tended to be nearly constant. In conclusion, our results suggest that the threshold value should be carefully considered when quantifying CBF in terms of absolute values using DSC-MRI for DA based on SVD. We believe that this study will be helpful in selecting the threshold value in SVD.
A portion of HIV-infected patients under therapy with protease inhibitors (HIV PIs) concomitantly consume or abuse alcohol leading to hepatic injury. The underling mechanisms are not known. We hypothesize that HIV PI aggravates alcohol-induced liver injury through an endoplasmic reticulum (ER) stress mechanism. To address this, we treated mice and primary mouse and human hepatocytes (PMH and PHH respectively) with alcohol and the two HIV PIs: ritonavir and lopinavir. In mice, ritonavir and lopinavir (15 mg/kg body weight each) induced mild ER stress and inhibition of Sarco/ER Calcium-ATPase (SERCA) without significant increase in serum ALT levels. However, a single dose of alcohol by gavage (5g/kg body weight) plus the two HIV PIs caused a greater than 5-fold increase in serum ALT, a synergistic increase in alcohol-induced liver lipid accumulation and ER stress response, and a decrease of SERCA. Mice treated with chronic HIV PIs and alcohol developed moderate liver fibrosis. In PMH, the HIV drugs plus alcohol also inhibited SERCA expression and increased expression of GRP78, CHOP, SREBP1c and phosphorylated JNK2, which were accompanied by a synergistic increase in cell death compared to alcohol or the HIV drugs alone. In PHH, ritonavir and lopinavir or alcohol alone treatment increased mRNA of spliced Xbp1 and decreased SERCA, which were accompanied by reduced levels of intracellular calcium. Alcohol combined with the HIV drugs significantly reduced intracellular calcium levels and potentiated cell death, which was comparable to the cell death caused by the SERCA inhibitor-thapsigargin. Our findings suggest the possibility that HIV PIs potentiate alcohol-induced ER stress and injury through modulation of SERCA and maintaining calcium homeostasis should be a therapeutic aim for a better care of HIV patients.
Betaine-homocysteine methyltransferase (BHMT) regulates homocysteine levels in the liver. We previously reported that the alteration of BHMT is associated with alcoholic liver steatosis and injury. In this study, we tested whether BHMT protects hepatocytes from homocysteine-induced injury and lipid accumulation. Both BHMT transfectants of HepG2 cells and primary mouse hepatocytes with suppressed BHMT were generated. Comparisons were made between the cell models with respect to their response to homocysteine treatments. is a cytosolic zinc metalloenzyme that is highly expressed in the liver and kidneys. 1-6 BMHT catalyzes methyl transfer from betaine, a product of choline oxidation, to homocysteine, yielding methionine and N,N-dimethylglycine. Homocysteine remethylation is also catalyzed by a cobalamin-dependent enzyme, methionine synthase (MS), with 5-methylfolate as a cosubstrate supplied by 5,10-methylenetetrahydrofolate reductase. Both BHMT and MS have a low Michaelis-Menten constant (K m ) for homocysteine. Elevated S-adenosylmethionine (SAM), resulting from a methionine excess, inhibits BHMT and the formation of 5-methyltetrahydrofolate catalyzed by 5,10-methylenetetrahydrofolate reductase. 7 Hence, homocysteine remethylation is predominant at low levels of homocysteine and methionine. At high levels, SAM stimulates 2 high-K m enzymes, methionine adenosyltransferase-III and cystathionine -synthase (CBS). The latter converts homocysteine toward the transsulfuration pathway for
Chronic ethanol infusion resulted in greater serum alanine aminotransferase elevation, lipid accumulation, necroinflammation, and focal hepatic cell death in mice than rats. Mice exhibited a remarkable hyperhomocysteinemia but no increase was seen in rats. Similarly, a high-methionine low-folate diet (HMLF) induced less steatosis, serum alanine aminotransferase increase, and hyperhomocysteinemia in rats than in mice. Western blot analysis of betaine homocysteine methyltransferase (BHMT) expression showed that rats fed either ethanol or HMLF had significantly increased BHMT expression, which did not occur in mice. Nuclear factor-B p65 was increased in mouse in response to alcohol feeding. The human BHMT promoter was repressed by homocysteine in mouse hepatocytes but not rat hepatocytes. BHMT induction was faster and greater in primary rat hepatocytes than mouse hepatocytes in response to exogenous homocysteine exposure. Mice fed ethanol intragastrically exhibited an increase in glucose-regulated protein 78 and inositol-requiring enzyme 1, which was not seen in the rat, and sterol regulatory element binding protein 1 was increased to a greater extent in mice than rats. Thus, rats are more resistant to ethanol-induced steatosis, endoplasmic reticulum stress, and hyperhomocysteinemia, and this correlates with induction of BHMT in rats. Conclusion: These findings support the hypothesis that a critical factor in the pathogenesis of alcoholic liver injury is the enhanced ability of rat or impaired ability of mouse to up-regulate BHMT which prevents hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury. ( T he sulfhydryl-containing amino acid homocysteine (Hcy) is an intermediate of normal methionine metabolism. Hcy has unique biochemical properties that can both support a wide range of molecular effects and promote oxidant stress. Elevated Hcy in the blood, a condition termed hyperhomocysteinemia (HHcy) is implicated in a variety of diseases including vascular, central nervous system, and liver disease. 1-4 Accumulating evidence links hyperhomocysteinemia to endoplasmic reticulum (ER) stress in diet models and in both knockout mice and humans with altered Hcy metabolism. 5,6 In all models of nonalcoholic HHcy (5,10-methylene tetrahydrofolate reductase [MTHFR] Ϫ/Ϫ, cystathionine -synthase [CBS] ϩ/Ϫ, high-methionine/low-folate diet), hepatic steatosis and ER stress with variable necroinflammation and apoptosis are observed. [7][8][9][10][11] Our previous work has particularly linked HHcy to alcoholic liver injury. The intragastric alcohol feeding exhibited a striking 5-fold to 10-fold increase in mouse plasma Hcy which was associated with ER stress response as indicated by altered expression of a set of ER stress markers such as molecular chaperone glucose-regulated protein 78 (GRP78 or BiP), sterol regulatory element binding proteins (SREBPs) that regulate liver lipid synthesis, and CCAAT-enhanced binding protein (C/EBP)-homologous protein (CHOP or GADD153) that mediates cell death. [12][13][14][15]
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.