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Hepatology International

, Volume 12, Issue 2, pp 97–106 | Cite as

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

  • Alexander J. Kovalic
  • Sanjaya K. Satapathy
  • Naga Chalasani
Review Article

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.

Keywords

Non-alcoholic fatty liver disease Non-alcoholic steatohepatitis Incretin GLP-1 DPP-4 ASK1 

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

Notes

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.

Compliance with ethical standards

Conflict of interest

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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Copyright information

© Asian Pacific Association for the Study of the Liver 2018

Authors and Affiliations

  1. 1.Department of Internal MedicineWake Forest Baptist Medical CenterWinston-SalemUSA
  2. 2.Division of Transplant Surgery, Department of SurgeryMethodist University Hospital Transplant Institute, University of Tennessee Health Science CenterMemphisUSA
  3. 3.Department of Medicine, Division of Gastroenterology and HepatologyIndiana University School of MedicineIndianapolisUSA

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