Pharmacotherapy for NASH: Current and emerging

Konerman, Monica A.; Jones, Jacob C.; Harrison, Stephen A.

doi:10.1016/j.jhep.2017.10.015

Cited by 261 publications

(243 citation statements)

References 71 publications

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“…When validated in randomized clinical trials, only a few drugs have shown efficacy on NASH liver histology and/or fibrosis. These include vitamin E, pioglitazone (PPARγ agonist), obeticholic acid (farensoid X receptor agonist), cenicriviroc (CCR2/CCR5 antagonist), selonsertib (apoptosis signal-regulating kinase 1 inhibitor), and liraglutide (glucagon-like peptide 1 analogue) [136–141]. However, adverse effects may limit the treatment potential, e.g., glitazones are associated with phenotypical weight gain [136] and obeticholic acid induced pruritus and elevated LDL-C [137], the latter a potential concern in patients already at risk for cardiovascular disease.…”

Section: Pre-clinical Models and Current Clinical Managementmentioning

confidence: 99%

Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

Ipsen

Lykkesfeldt

Tveden‐Nyborg

2018

Cell. Mol. Life Sci.

1,002

757

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Non-alcoholic fatty liver disease (NAFLD) is currently the world’s most common liver disease, estimated to affect up to one-fourth of the population. Hallmarked by hepatic steatosis, NAFLD is associated with a multitude of detrimental effects and increased mortality. This narrative review investigates the molecular mechanisms of hepatic steatosis in NAFLD, focusing on the four major pathways contributing to lipid homeostasis in the liver. Hepatic steatosis is a consequence of lipid acquisition exceeding lipid disposal, i.e., the uptake of fatty acids and de novo lipogenesis surpassing fatty acid oxidation and export. In NAFLD, hepatic uptake and de novo lipogenesis are increased, while a compensatory enhancement of fatty acid oxidation is insufficient in normalizing lipid levels and may even promote cellular damage and disease progression by inducing oxidative stress, especially with compromised mitochondrial function and increased oxidation in peroxisomes and cytochromes. While lipid export initially increases, it plateaus and may even decrease with disease progression, sustaining the accumulation of lipids. Fueled by lipo-apoptosis, hepatic steatosis leads to systemic metabolic disarray that adversely affects multiple organs, placing abnormal lipid metabolism associated with NAFLD in close relation to many of the current life-style-related diseases.

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Section: Pre-clinical Models and Current Clinical Managementmentioning

confidence: 99%

Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

Ipsen

Lykkesfeldt

Tveden‐Nyborg

2018

Cell. Mol. Life Sci.

1,002

757

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“…Currently, the treatment of NAFLD is divided into three main categories: one is lifestyle changes, such as dietary adjustments, and increased physical activity; the second is control by clinical drugs; and the third is surgical intervention [3,12,34]. For the patient as a whole, changes in diet, energy intake control and increased exercise are still the first-line choice.…”

Section: Discussionmentioning

confidence: 99%

“…Although the progression of liver fibrosis is relatively slower in patients with NASH than in patients with chronic viral hepatitis and primary biliary cirrhosis, the prognosis of NASH-related cirrhosis is similar to that for causes of cirrhosis and patients with NASH may be more susceptible to aging and metabolic syndrome-related liver failure and hepatocellular carcinoma [8][9][10]. Therefore, identification of cellular and molecular processes of NASH pathogenesis is of great importance to identify novel therapeutic targets for this highly prevalent and potentially serious disease [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Cangju Qinggan Jiangzhi Decoction Reduces the Development of NonAlcoholic Steatohepatitis and Activation of Kupffer Cells

Cheng

Chen

Jian

et al. 2018

Cell Physiol Biochem

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Background/Aims: Nonalcoholic steatohepatitis (NASH) is defined as lipid accumulation with hepatic injury, inflammation and early to moderate fibrosis. Kupffer cells play a crucial role in promoting hepatic inflammation, which further facilitates the development of NASH. Here we investigated the effects of Cangju Qinggan Jiangzhi decoction (CQJD) on high fat diet (HFD) and methionine-choline deficient (MCD) induced mouse NASH pathogenesis. Methods: Mouse NASH models were developed by HFD and MCD diet. The treated mice were divided into three groups: the control group (n = 10), the low-dose CQJD treatment group (n = 10) and the high-dose CQJD treatment group (n = 10). The hepatic injury, inflammation, and apoptotic molecules were evaluated by H&E staining, immunohistochemistry and real-time PCR. Kupffer cells were isolated from control mice and CQJD-treated mice after stimulation by lipopolysaccharide (LPS) and/or palmitic acid. The level of the inflammatory cytokines TNFα, IL1β, and CCL2 was measured by ELISA. Results: The HFD-fed mice displayed significant metabolic, inflammatory, and oxidative stress-related alterations due to hepatic lipid accumulation. CQJD treatment largely normalized the hepatic injury, lowered the ALT/AST level, and reduced the severity of liver inflammation, as revealed by the decreased inflammatory cytokines levels. In vitro, CQJD blocked the activation of LPS- or palmitic acid-primed Kupffer cells in a dose-dependent manner. In the MCD diet-induced NASH mice, similar therapeutic effects of CQJD were also observed. Conclusion: CQJD ameliorates mouse nonalcoholic steatohepatitis. The reduction in liver injury and inflammation induced by CQJD is associated with reduced activation of Kupffer cells. Our results suggest that CQJD is a promising therapeutic strategy in clinical steatohepatitis.

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“…Importantly, concentrations of saturated fatty acid (e.g., palmitic acid), ceramide, LPC, or free cholesterol are increased in the livers of human subjects with NASH (27, 33, 34) and of animals with NASH (35), suggesting that free saturated fatty acids and other lipid metabolites as mentioned above contribute to the development and progression of NASH. Numerous studies suggest that therapeutic approaches to inhibit hepatic lipid accumulation, lipid-induced oxidative stress, and lipotoxicity-mediated cell death are promising strategies for treatment of NAFLD/NASH (36, 37). Phase 1, 2a, 2b, and 3 trials are being undertaken to test peroxisome proliferator activated receptor alpha/delta (PPARα/δ) activator (Elafibranor/GFT505; Clinical Trials NCT02704403), liver X receptor alpha (LXRα) inhibitor (Oltipraz; NCT02068339), acetyl-CoA carboxylase (ACC) inhibitors (GS-0976; NCT02856555 and PF-05221304; NCT03248882), stearoyl-CoA desaturase 1 (SCD1) inhibitor (Aramchol; NCT02279524), diacylglycerol acyltransferase 1 (DGAT1) inhibitor (Pradigastat/LCQ908; NCT01811472), and DGAT2 inhibitor (PF-06865571; NCT03513588) as targeting strategies to reduce hepatic steatosis in NASH patients via enhancement of β-oxidation or inhibition of fatty acid/TG synthesis.…”

Section: “Multiple-parallel Hit” Pathogenesis Of Nashmentioning

confidence: 99%

Pathogenesis of Nonalcoholic Steatohepatitis and Hormone-Based Therapeutic Approaches

Kim

Lee

2018

Front. Endocrinol.

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Non-alcoholic fatty liver disease (NAFLD) is an emerging global health problem and a potential risk factor for type 2 diabetes, cardiovascular disease, and chronic kidney disease. Nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD, is a predisposing factor for development of cirrhosis and hepatocellular carcinoma. The increasing prevalence of NASH emphasizes the need for novel therapeutic approaches. Although therapeutic drugs against NASH are not yet available, fundamental insights into the pathogenesis of NASH have been made during the past few decades. Multiple therapeutic strategies have been developed and are currently being explored in clinical trials or preclinical testing. The pathogenesis of NASH involves multiple intracellular/extracellular events in various cell types in the liver or crosstalk events between the liver and other organs. Here, we review current findings and knowledge regarding the pathogenesis of NASH, focusing on the most recent advances. We also highlight hormone-based therapeutic approaches for treatment of NASH.

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Pharmacotherapy for NASH: Current and emerging

Cited by 261 publications

References 71 publications

Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

Cangju Qinggan Jiangzhi Decoction Reduces the Development of NonAlcoholic Steatohepatitis and Activation of Kupffer Cells

Pathogenesis of Nonalcoholic Steatohepatitis and Hormone-Based Therapeutic Approaches

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