Yeungnam Univ J Med.  2019 May;36(2):67-77. 10.12701/yujm.2019.00171.

Pharmacologic therapy for nonalcoholic steatohepatitis focusing on pathophysiology

• Yoon IC
• Eun JR

• KMID: 2449317
• DOI: http://doi.org/10.12701/yujm.2019.00171

Abstract

The paradigm of chronic liver diseases has been shifting. Although hepatitis B and C viral infections are still the main causes of liver cirrhosis and hepatocellular carcinoma (HCC), the introduction of effective antiviral drugs may control or cure them in the near future. In contrast, the burden of nonalcoholic fatty liver disease (NAFLD) has been increasing for decades, and 25 to 30% of the general population in Korea is estimated to have NAFLD. Over 10% of NAFLD patients may have nonalcoholic steatohepatitis (NASH), a severe form of NAFLD. NASH can progress to cirrhosis and HCC. NASH is currently the second leading cause to be placed on the liver transplantation list in the United States. NAFLD is associated with obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome. The pathophysiology is complex and associated with lipotoxicity, inflammatory cytokines, apoptosis, and insulin resistance. The only proven effective treatment is weight reduction by diet and exercise. However, this may not be effective for advanced fibrosis or cirrhosis. Therefore, effective drugs are urgently needed for treating these conditions. Unfortunately, no drugs have been approved for the treatment of NASH. Many pharmaceutical companies are trying to develop new drugs for the treatment of NASH. Some of them are in phase 2 or 3 clinical trials. Here, pharmacologic therapies in clinical trials, as well as the basic principles of drug therapy, will be reviewed, focusing on pathophysiology.

Keyword

Drug therapy; Nonalcoholic steatohepatitis; Pathophysiology

MeSH Terms

Antiviral Agents
Apoptosis
Carcinoma, Hepatocellular
Cytokines
Diet
Drug Therapy
Dyslipidemias
Fibrosis
Hepatitis B
Humans
Insulin Resistance
Korea
Liver Cirrhosis
Liver Diseases
Liver Transplantation
Non-alcoholic Fatty Liver Disease*
Obesity
United States
Weight Loss
Antiviral Agents
Cytokines

Figure

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  Fig. 1. Lipotoxicity. Although the major form of lipids is TG, other lipid metabolites also accumulate: FFAs, FC, diacylglycerol, CE, and ceramide. “The quality” rather than “quantity” of lipids may contribute to lipotoxicity. Especially, FC and FFAs are important mediators of lipotoxicity. They up-regulate death receptors, then sensitizing them to TNF-α. They also trigger ER stress, causing mitochondrial dysfunction and apoptosis (adapted from Okazaki I. [Non-alcoholic steatohepatitis]. Cho YK, Eun JR, translators. Paju: Koonja Publishing Inc.; 2018. p. 152 [5], with permission of Koonja Publishing Inc.). TG, triglyceride; FFA, free fatty acid; FC, free cholesterol; CE, cholesterol ester; TNF-α, tumor necrosis factor-α; ER, endoplasmic reticulum; TNF-R1, tumor necrosis factor receptor 1; TRAIL-R, TNF-related apoptosis-inducing ligand receptor; ROS, reactive oxygen species.

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  Fig. 2. Basic concept of apoptosis. Apoptosis is a key consequence of cell injury. There are two pathways: extrinsic pathway via death-receptors, such as the TNF-α receptor, Fas, and TRAIL; and the intrinsic pathway via ER stress. Both pathways go through the mitochondria. Mitochondrial dysfunction is a key event of apoptosis. Caspases are enzymes associated with the apoptotic process. Caspase 8 is an initiator caspase and caspase 3/7 is an effector caspase. The Bcl2 family is also involved with apoptosis. Bid, Bad, Bim, and Bax/Bak are pro-apoptotic and Bcl2 and Bcl-xL are anti-apoptotic. Caspase 8 occurs cleavage of Bid to tBid, leading to mitochondrial permeabilization and the release of cytochrome C. Released cytochrome C activates caspase 3/7, the effector caspase, resulting in the final apoptotic morphology (adapted from Okazaki I. [Non-alcoholic steatohepatitis]. Cho YK, Eun JR, translators. Paju: Koonja Publishing Inc.; 2018. p. 151 [5], with permission of Koonja Publishing Inc.). TNF-α, tumor necrosis factor-α; TRAIL, TNF-related apoptosis-inducing ligand; ER, endoplasmic reticulum; tBid, truncated Bid; ROS, reactive oxygen species.

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  Fig. 3. TGF-β signaling in steatohepatitis. Even hepatocytes, as well as Kupffer cells, phagocytize apoptotic cell debris. They release TGF-β, the main cytokine in fibrosis, which causes the activation of HSCs and more accumulation of lipids in hepatocytes via Smad2/3 (adapted from Okazaki I. [Non-alcoholic steatohepatitis]. Cho YK, Eun JR, translators. Paju: Koonja Publishing Inc.; 2018. p. 154 [5], with permission of Koonja Publishing Inc.). TGF-β, transforming growth factor-β; HSC, hepatic stellate cell.

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  Fig. 4. ASK1 and insulin resistance. The inflammatory cytokine, TNF-α, produces mitochondrial ROS, which activates ASK1. ASK1 activates JNK, and subsequently causes serine phosphorylation of IRS-1. Normally, the tyrosine phosphorylation of IRS-1 is a key event in the action of insulin. Impaired tyrosine phosphorylation and increased serine phosphorylation of IRS-1 are associated with insulin resistance. ASK1, apoptosis signal-regulating kinase 1; TNF-α, tumor necrosis factor-α; ROS, reactive oxygen species; JNK, c-Jun-NH2-terminal kinases; IRS-1, insulin receptor substrate-1; ROS, reactive oxygen species.

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  Fig. 5. Lysyl oxidase. The LOX family is composed of four isoforms, LOX and the LOXL1-4. Among them, LOXL2 is a stabilizer of collagen crosslinking. LOXL2 is also expressed in hepatic progenitor cells in fibrotic liver. LOXL2 promotes progenitor cells towards fibrogenic cholangiocytes, suppressing their differentiation into hepatocytes. The ductular reaction characterized by reactive cholangiocytes is associated with hepatocarcinogenesis (adapted from Okazaki I. [Non-alcoholic steatohepatitis]. Cho YK, Eun JR, translators. Paju: Koonja Publishing Inc.; 2018. p. 225 [5], with permission of Koonja Publishing Inc.). LOX, lysyl oxidase; LOXL1-4, LOX-like 1-4; HCC, hepatocellular carcinoma; HPC, hepatic progenitor cell.

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  Fig. 6. Farnesoid X receptor. The primary bile acids, CA, and CDCA, are synthesized in the liver and secreted into the bile duct. The CYP7A1 is key for this process. Approximately 95% of the primary bile acids are reabsorbed in the ileum. A small proportion (~5%) enters the colon. Here, secondary bile acids are metabolized by intestinal microbiota. The majority of the bile acids are re-used by the enterohepatic circulation and only some are newly-synthesized. The FXR is a key nuclear receptor for bile acid resorption in the ileum. FXR stimulates FGF-19 in the enterocytes, which inhibits CYP7A1, resulting in reduced new bile acid synthesis by negative feedback. The FXR nuclear receptors are also expressed in the liver, adrenal glands and kidneys. In the liver, FXR acts via a SHR. Intrahepatic FXR/SHP represses bile acid synthesis by inhibiting CYP7A1 and TG synthesis by inhibiting SREBP-1c. It also stimulates the β-oxidation of FFAs by PPAR-α activation, increases glycogenesis and suppresses glycolysis. Intestinal FXR induces FGF-19, which increases insulin sensitivity by GLP-1 activation (adapted from Okazaki I. [Non-alcoholic steatohepatitis]. Cho YK, Eun JR, translators. Paju: Koonja Publishing Inc.; 2018. p. 225 [5], with permission of Koonja Publishing Inc.). CA, cholic acid; CDCA, chenodeoxycholic acid; CYP7A1, cytochrome P450 7A1; FXR, farnesoid X receptor; FGF-19, fibroblast growth factor 19; SHR, short heterodimer partner; SHP, short heterodimer partner; TG, triglyceride; FFA, free fatty acid; PPAR-α, peroxisome proliferator-activated receptor-α; GLP-1, glucagon-like peptide-1; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; SREBP-1, sterol-responsive element binding protein-1; SCD1, steroyl coenzyme A desaturase 1; DCA, deoxycholic acid; UCDA, ursodeoxycholic acid.

Reference

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