Effects of Natural Products on Fructose-Induced Nonalcoholic Fatty Liver Disease (NAFLD)

Abstract

As a sugar additive, fructose is widely used in processed foods and beverages. Excessive fructose consumption can cause hepatic steatosis and dyslipidemia, leading to the development of metabolic syndrome. Recent research revealed that fructose-induced nonalcoholic fatty liver disease (NAFLD) is related to several pathological processes, including: (1) augmenting lipogenesis; (2) leading to mitochondrial dysfunction; (3) stimulating the activation of inflammatory pathways; and (4) causing insulin resistance. Cellular signaling research indicated that partial factors play significant roles in fructose-induced NAFLD, involving liver X receptor (LXR)α, sterol regulatory element binding protein (SREBP)-1/1c, acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD), peroxisome proliferator-activated receptor α (PPARα), leptin nuclear factor-erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNF-α), c-Jun amino terminal kinase (JNK), phosphatidylinositol 3-kinase (PI3K) and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Until now, a series of natural products have been reported as regulators of NAFLD in vivo and in vitro. This paper reviews the natural products (e.g., curcumin, resveratrol, and (-)-epicatechin) and their mechanisms of ameliorating fructose-induced NAFLD over the past years. Although, as lead compounds, natural products usually have fewer activities compared with synthesized compounds, it will shed light on studies aiming to discover new drugs for NAFLD.

Keywords: fructose-induced NAFLD; inflammatory pathways; insulin resistance; lipogenesis; mitochondrial dysfunction; natural products.

Figure 1

Schematic representation of underlying mechanisms of fructose-induced NAFLD. Fructose may stimulate NAFLD through different pathological processes, including: (1) augmenting lipogenesis through up-regulating liver X receptor (LXR)α and sterol regulatory element binding protein (SREBP)-1c; (2) leading to mitochondrial dysfunction by depressing peroxisome proliferator-activated receptor α (PPARα) and nuclear factor-erythroid 2-related factor 2 (Nrf2); (3) stimulating the activation of inflammatory pathways; and (4) causing insulin resistance. ACC: acetyl-CoA carboxylase; ACLY: ATP-citrate lyase; AKT: protein kinase B; AMPK: adenosine 5′-monophosphate (AMP)-activated protein kinase; ATGL: adipose triglyceride lipase; CPT: carnitine palmitoyl transferase; DGAT: diacylglycerol acyltransferase; FAS: fatty acid synthase; Fru: fructose; FFA: free fatty acid; GPAT: glycerol-3-phosphate acyltransferase; HSL: hormone-sensitive lipase; IKK: inhibitor of nuclear factor κB (IκB) kinase; IL-6: interleukin 6; iNOS: inducible nitric oxide synthase; IRS1: insulin receptor substrate-1; JNK: c-Jun amino terminal kinase; LKB1: Liver kinase B1; MCD: malonyl-CoA decarboxylase; mTOR: mammalian target of rapamycin NF-κB: nuclear factor kappa B; NO: nitric oxide; PI3K: phosphoinositide 3-kinase; PKA/C: Protein kinase A/C; ROS: reactive oxygen species; SCD: stearoyl-CoA desaturase; TAG: triacylglycerol; TNF-α: tumor necrosis factor α.