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Targeting incretin hormones and the ASK-1 pathway as therapeutic options in the treatment of non-alcoholic steatohepatitis

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is currently one of the leading forms of chronic liver disease, and its rising frequency worldwide has reached epidemic proportions. NAFLD, particularly its progressive variant NASH (non-alcoholic steatohepatitis), can lead to advanced fibrosis, cirrhosis, and HCC. The pathophysiologic mechanisms that contribute to the development and progression of NAFLD and NASH are complex, and as such myriad therapies are under investigation targeting different pathophysiological mechanisms. Incretin-based therapies, including GLP-1RAs and DPP-4 inhibitors and the inhibition of ASK1 pathway have provided two such novel mechanisms in the management of this disease, and will remain focus of this review.

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Abbreviations

AAV8:

Adeno-associated virus vector 8

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

ASK-1:

Apoptosis signal-regulating kinase-1 (also known as MAP3K5)

BMI:

Body mass index

Cdc25A/C:

Cell division cycle 25A/C

CFLAR:

CASP8 and FADD-like apoptosis regulator (also known as c-FLIP)

CHOP:

CCAAT/enhancer-binding protein (C/EBP) homologous protein

CREG:

Cellular repressor of E1A-stimulated genes

CT:

Computed tomography

DKK3:

Dickkopf-related protein 3

DPP-4:

Dipeptidyl peptidase-4

ER:

Endoplasmic reticulum

FFA:

Free fatty acid

GIP:

Glucose-dependent insulinotropic polypeptide

GLP-1:

Glucagon-like peptide-1

GLP-1R:

Glucagon-like peptide-1 receptor

GLP-1RA:

Glucagon-like peptide-1 receptor agonist

HCC:

Hepatocellular carcinoma

HFD:

High fat diet

HgA1c:

Hemoglobin A1c

HNF4α:

Hepatocyte nuclear factor 4α

HOMA-IR:

Homeostatic model assessment of insulin resistance

IL-6:

Interleukin 6

IRS1:

Insulin receptor substrate 1

JNK1:

c-Jun N-terminal kinase 1

LDL:

Low density lipoprotein

LOXL2:

Lysyl oxidase-like molecule 2

MAPK:

Mitogen-activated protein kinase

MKK:

Mitogen-activated protein kinase kinase

MRI:

Magnetic resonance imaging

MRE:

MRI elastography

NAC:

N-acetyl-cysteine

NAFLD:

Non-alcoholic fatty liver disease

NAS:

NAFLD activity score

NASH:

Non-alcoholic steatohepatitis

PDFF:

Proton density fat fraction

PP5:

Serine/threonine protein phosphatase 5

PPARα:

Peroxisome proliferator-activated receptor alpha

RCT:

Randomized controlled trial

ROS:

Reactive oxygen species

T2DM:

Type 2 diabetes mellitus

TNF:

Tumor necrosis factor

TRAF1:

TNF receptor-associated factor 1

TRX:

Thioredoxin

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Funding

No Grants or financial support was used in the writing of this manuscript. Dr. Chalasani has consulting agreements and research Grants with several pharmaceutical companies but none represent relevant conflict of interest for this invited review article. Dr. Satapathy has received Grant/research support from Biotest, Conatus, Genfit, Gilead Sciences, Intercept, and Shire; served on the advisory panel for Abbvie, Gilead Sciences, and Intercept; and Speakers bureau for Alexion, and Intercept pharma. None represent relevant conflict of interest for this invited review article.

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Authors and Affiliations

  1. Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA

    Alexander J. Kovalic

  2. Division of Transplant Surgery, Department of Surgery, Methodist University Hospital Transplant Institute, University of Tennessee Health Science Center, Memphis, TN, USA

    Sanjaya K. Satapathy

  3. Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA

    Naga Chalasani

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  1. Alexander J. Kovalic
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  2. Sanjaya K. Satapathy
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  3. Naga Chalasani
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Correspondence to Naga Chalasani.

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This review article is in compliant with general ethical considerations considered applicable for a review article. Alexander J. Kovalic, Sanjaya K. Satapathy and Naga Chalasani declare no financial conflicts of interest.

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Kovalic, A.J., Satapathy, S.K. & Chalasani, N. Targeting incretin hormones and the ASK-1 pathway as therapeutic options in the treatment of non-alcoholic steatohepatitis. Hepatol Int 12, 97–106 (2018). https://doi.org/10.1007/s12072-018-9854-1

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