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Review
. 2014 Nov 27;6(11):800-11.
doi: 10.4254/wjh.v6.i11.800.

Pathogenesis and therapeutic approaches for non-alcoholic fatty liver disease

Hye-Jin Yoon  1 , Bong Soo Cha  1
Affiliations
Review

Pathogenesis and therapeutic approaches for non-alcoholic fatty liver disease

Hye-Jin Yoon et al. World J Hepatol. .

Abstract

Non-alcoholic fatty liver disease affects approximately one-third of the population worldwide, and its incidence continues to increase with the increasing prevalence of other metabolic disorders such as type 2 diabetes. As non-alcoholic fatty liver disease can progress to liver cirrhosis, its treatment is attracting greater attention. The pathogenesis of non-alcoholic fatty liver disease is closely associated with insulin resistance and dyslipidemia, especially hypertriglyceridemia. Increased serum levels of free fatty acid and glucose can cause oxidative stress in the liver and peripheral tissue, leading to ectopic fat accumulation, especially in the liver. In this review, we summarize the mechanism underlying the progression of hepatic steatosis to steatohepatitis and cirrhosis. We also discuss established drugs that are already being used to treat non-alcoholic fatty liver disease, in addition to newly discovered agents, with respect to their mechanisms of drug action, focusing mainly on hepatic insulin resistance. As well, we review clinical data that demonstrate the efficacy of these drugs, together with improvements in biochemical or histological parameters.

Keywords: Drugs; Insulin resistance; Non-alcoholic fatty liver disease; Pathogenesis.

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Figures

Figure 1
Figure 1
Mechanism of hepatic insulin resistance and the key pathway of drug action. Delivery of FFAs to the liver and skeletal muscle is increased in insulin resistance conditions, and these are metabolized via mitochondrial β-oxidation. Consequently, hyperglycemia and increased hepatic FFA uptake reduce glucose uptake and oxidation in skeletal muscle. Diet and exercise are the main treatment strategies for this pathogenesis; insulin sensitizers and MUFA may contribute to reducing peripheral insulin resistance. Pioglitazone and fenofibrate act on β-oxidation of mitochondria and reduce hepatic steatosis. Accelerated β-oxidation also causes increased production of ROS. Vitamin E can reduce oxidative stress. Adipose tissue inflammation of the liver leads to inflammatory activation of hepatic Kupffer cells via classic response (M1) and produce inflammatory cytokines. This is also associated with decreased adiponectin levels and promotes hepatic steatohepatitis. Pentoxifylline inhibits TNF-α and alleviates steatohepatitis. Hyperglycemia caused by insulin resistance up-regulates lipogenic gene expression, such as SREBP-1c and ChREBP, and induces lipogenesis in hepatocytes. Cilostasol may inhibit SREBP-1c. FFA: Free fatty acid; TG: Triglyceride; CPT-I: Carnitine palmitoyltransferase-I; ACC: Acetyl-CoA carboxylase; ATGL: Adipose triglyceride lipase; ChREBP: Carbohydrate responsive element binding protein; SREBP-1c: Sterol regulatory element binding protein-1c; TCA: Tricarboxylic acid; ROS: Reactive oxygen species; IRS: Insulin receptor substrate; DAG: Diacylglycerol; G-6-P: Glucose 6-phosphate; TNF-α: Tumor necrosis factor- α; MUFA: Monosaturated fatty acids; M1: Kupffer cells activated via classic pathway.
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