PCSK9 inhibition as a novel therapeutic target for alcoholic liver disease

AbstractAlcoholic liver disease (ALD) causes significant morbidity and mortality, and pharmacological treatment options are limited. In this study, we evaluated the PCSK9 inhibitor alirocumab, a monoclonal antibody that robustly reduces low-density lipoprotein cholesterol (LDL-C), for the treatment of ALD using a rat model of chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for 6 weeks to rats receiving a 12% alcohol liquid diet or an isocaloric control diet. At the end of the alcohol exposure protocol, serum and liver samples were obtained for molecular characterization and histopathological analysis. PCSK9 inhibition with alirocumab attenuated alcohol-induced hepatic triglyceride accumulation through regulation of lipid metabolism (mRNA expression of modulators of fatty acid synthesis (FAS) and catabolism (PPARα and CPT1)), hepatocellular injury (ALT), hepatic inflammation (mRNA expression of pro-inflammatory cytokines/chemokines (TNFa, IL-1β, IL-22, IL-33, IL-17α, IL-2, MIP-2, and MCP-1), and neutrophil infiltration (myeloperoxidase staining)). Alirocumab treatment also attenuated alcohol-induced PCSK9 mRNA elevation and upregulated LDL-receptor (LDL-R) via modulation of the transcription factors (SREBP-1, SREBP-2, and E2F1) in liver. We demonstrated that chronic anti-PCSK9 treatment using the monoclonal antibody alirocumab attenuated alcohol-induced steatohepatitis in the rat model. Given the large unmet clinical need for effective and novel treatments for ALD, anti-PCSK9 treatment with the monoclonal antibody that spares liver metabolism is a viable new therapeutic possibility. Future studies are needed to elucidate the exact role of PCSK9 in ALD and alcohol use disorder (AUD) and to evaluate efficacy and safety of anti-PCSK9 treatment in clinical populations with ALD/AUD.

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Probiotic and glutamine treatments attenuate alcoholic liver disease in a rat model

Experimental and Therapeutic Medicine ◽

10.3892/etm.2019.8123 ◽

2019 ◽

Cited By ~ 3

Author(s):

Huping Huang ◽

Zhihui Lin ◽

Yanling Zeng ◽

Xueyan Lin ◽

Yali Zhang

Keyword(s):

Liver Disease ◽

Alcoholic Liver Disease ◽

Rat Model

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Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease

Journal of Hepatology ◽

10.1016/j.jhep.2010.08.007 ◽

2011 ◽

Vol 54 (1) ◽

pp. 164-172 ◽

Cited By ~ 69

Author(s):

Zoltan Derdak ◽

Charles H. Lang ◽

Kristine A. Villegas ◽

Ming Tong ◽

Nicholas M. Mark ◽

...

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Alcoholic Liver Disease ◽

Rat Model

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Potential Contributions of the Tobacco Nicotine-Derived Nitrosamine Ketone (NNK) in the Pathogenesis of Steatohepatitis in a Chronic Plus Binge Rat Model of Alcoholic Liver Disease

Alcohol and Alcoholism ◽

10.1093/alcalc/agu083 ◽

2015 ◽

Vol 50 (2) ◽

pp. 118-131 ◽

Cited By ~ 20

Author(s):

V. Zabala ◽

M. Tong ◽

R. Yu ◽

T. Ramirez ◽

E. B. Yalcin ◽

...

Keyword(s):

Liver Disease ◽

Alcoholic Liver Disease ◽

Rat Model

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Modification of Heat Shock Protein 90 by 4-Hydroxynonenal in a Rat Model of Chronic Alcoholic Liver Disease

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.105.088088 ◽

2005 ◽

Vol 315 (1) ◽

pp. 8-15 ◽

Cited By ~ 117

Author(s):

David L. Carbone ◽

Jonathan A. Doorn ◽

Zachary Kiebler ◽

Brian R. Ickes ◽

Dennis R. Petersen

Keyword(s):

Liver Disease ◽

Heat Shock ◽

Heat Shock Protein ◽

Alcoholic Liver Disease ◽

Rat Model ◽

Heat Shock Protein 90 ◽

Chronic Alcoholic

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Defect of mitochondrial respiratory chain is a mechanism of ROS overproduction in a rat model of alcoholic liver disease: role of zinc deficiency

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00270.2015 ◽

2016 ◽

Vol 310 (3) ◽

pp. G205-G214 ◽

Cited By ~ 35

Author(s):

Qian Sun ◽

Wei Zhong ◽

Wenliang Zhang ◽

Zhanxiang Zhou

Keyword(s):

Mitochondrial Dna ◽

Liver Disease ◽

Zinc Deficiency ◽

Alcoholic Liver Disease ◽

Alcohol Exposure ◽

Ros Production ◽

Chronic Alcohol ◽

Respiratory Complexes ◽

Chronic Alcohol Exposure ◽

Mitochondrial Respiratory

Morphological and functional alterations of hepatic mitochondria have been documented in patients with alcoholic liver disease (ALD). Our recent study demonstrated that zinc level was decreased in whole liver and mitochondria by chronic alcohol feeding. The present study was undertaken to determine whether zinc deficiency mediates alcohol-induced mitochondrial electron transport chain (ETC) defect and whether defective ETC function may lead to generation of reactive oxygen species (ROS). Male Wistar rats were pair fed with the Lieber-DeCarli control or ethanol diet for 5 mo. Chronic alcohol exposure increased hepatic triglyceride, free fatty acid, and 4-hydroxynonenal (4HNE) levels; meanwhile hepatic mitochondrial 4HNE level was also increased. Moreover, hepatic mitochondrial respiratory complexes I, III, IV, and V and hepatic ATP production were decreased by chronic alcohol exposure. Chronic alcohol feeding decreased peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC1α), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), and mitochondrial DNA. HepG2 cells were treated with N, N, N′, N′-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) for 6 h. Zinc deficiency significantly decreased mitochondrial respiratory complexes I, III, and IV. In addition, PGC1α, NRF1, and TFAM levels as well as mitochondrial DNA were significantly decreased by TPEN treatment. Knockdown of mitochondrial respiratory complexes I, III, or IV by shRNA caused a decrease in mitochondrial membrane potential and an increase in ROS production. These results suggest that alcohol-induced hepatic zinc deficiency could inactivate mitochondrial biogenesis pathway and decrease mitochondrial DNA replication, which, in turn, decreases mitochondrial complex protein expression. The defect of mitochondrial respiratory complexes may worsen alcohol-induced ROS production.

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Oxidation of fish oil exacerbates alcoholic liver disease by enhancing intestinal dysbiosis in mice

Communications Biology ◽

10.1038/s42003-020-01213-8 ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 1

Author(s):

Ruibing Feng ◽

Li-Juan Ma ◽

Meng Wang ◽

Conghui Liu ◽

Rujie Yang ◽

...

Keyword(s):

Liver Disease ◽

Liver Injury ◽

Fish Oil ◽

Alcoholic Liver Disease ◽

Alcohol Exposure ◽

Sequencing Analysis ◽

Hepatic Inflammation ◽

Barrier Dysfunction ◽

Intestinal Dysbiosis ◽

Junction Protein

AbstractThe role of n-3 polyunsaturated fatty acids (PUFAs) in alcoholic liver disease (ALD) has been controversial. N-3 PUFA oxidation in animal feeding stuffs was rarely concerned, likely contributing to inconsistent outcomes. Here, we report the impacts of oxidized fish oil (OFO) on ALD in C57BL/6 mice. Alcohol exposure increased plasma aminotransferase levels and hepatic inflammation. These deleterious effects were ameliorated by unoxidized FO but exacerbated by OFO. Sequencing analysis showed the accentuated intestinal dysbiosis and the increased proportion of Proteobacteria in OFO-fed mice. Intestinal sterilization by antibiotics completely abolished OFO-aggravated liver injury. Additionally, alcohol exposure leads to the greater increase in plasma endotoxin and decrease in intestinal tight junction protein expressions in OFO-fed mice. Stabilization of intestinal barrier by obeticholic acid markedly blunted OFO-aggravated liver injury in alcohol-fed mice. These results demonstrate that OFO exacerbates alcoholic liver injury through enhancing intestinal dysbiosis, barrier dysfunction, and hepatic inflammation mediated by gut-derived endotoxin.

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Hepatic microtubule acetylation and stability induced by chronic alcohol exposure impair nuclear translocation of STAT3 and STAT5B, but not Smad2/3

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00071.2012 ◽

2012 ◽

Vol 303 (12) ◽

pp. G1402-G1415 ◽

Cited By ~ 10

Author(s):

David J. Fernandez ◽

Dean J. Tuma ◽

Pamela L. Tuma

Keyword(s):

Liver Disease ◽

Alcoholic Liver Disease ◽

Transforming Growth Factor ◽

Nuclear Translocation ◽

Trichostatin A ◽

Alcohol Exposure ◽

Transforming Growth Factor Β ◽

Ethanol Exposure ◽

Microtubule Attachment ◽

Deacetylase Inhibitor

Although alcoholic liver disease is clinically well described, the molecular basis for alcohol-induced hepatotoxicity is not well understood. Previously, we found that alcohol exposure led to increased microtubule acetylation and stability in polarized, hepatic WIF-B cells and in livers from ethanol-fed rats. Because microtubules are known to regulate transcription factor nuclear translocation and dynamic microtubules are required for translocation of at least a subset of these factors, we examined whether alcohol-induced microtubule acetylation and stability impair nuclear translocation. We examined nuclear delivery of factors representing the two mechanisms by which microtubules regulate translocation. To represent factors that undergo directed delivery, we examined growth hormone-induced STAT5B translocation and IL-6-induced STAT3 translocation. To represent factors that are sequestered in the cytoplasm by microtubule attachment until ligand activation, we examined transforming growth factor-β-induced Smad2/3 translocation. We found that ethanol exposure selectively impaired translocation of the STATs, but not Smad2/3. STAT5B delivery was decreased to a similar extent by addition of taxol (a microtubule-stabilizing drug) or trichostatin A (a deacetylase inhibitor), agents that promote microtubule acetylation in the absence of alcohol. Thus the alcohol-induced impairment of STAT nuclear translocation can be explained by increased microtubule acetylation and stability. Only ethanol treatment impaired STAT5B activation, indicating that microtubules are not important for its activation by Jak2. Furthermore, nuclear exit was not changed in treated cells, indicating that this process is also independent of microtubule acetylation and stability. Together, these results raise the exciting possibility that deacetylase agonists may be effective therapeutics for the treatment of alcoholic liver disease.

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