The Contribution of Hepatic NKT Cells to the Pathogenesis of Nonalcoholic Fatty Liver Disease

Review Article

J Hepat Res. 2014;1(3): 1013.

The Contribution of Hepatic NKT Cells to the Pathogenesis of Nonalcoholic Fatty Liver Disease

Tajiri K1* and Shimizu Y2

1Department of Gastroenterology, Toyama University Hospital, Japan

1Gastroenterology Unit, Nanto Municipal Hospital, Japan

*Corresponding author: Tajiri K, Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama 930-0194, Japan

Received: July 29, 2014; Accepted: September 13, 2014; Published: September 15, 2014


NKT cells are a unique subset of cells, which have both T cell receptors and surface molecules specific to natural killer cells, recognize glycolipid antigens, and have either pro- or anti-inflammatory activity. Recent findings showed that NKT cells play a regulatory role in various diseases involving lipid dysfunction, including Nonalcoholic Fatty Liver Disease (NAFLD), and contribute to the pathogenesis of these diseases. NKT cells are involved in the process of inflammation, due to interactions of CD1d with lipid metabolic and microbiota-derived factors, especially in NAFLD.

Keywords: NKT cell; CD1d; NAFLD, Glycolipid antigen; Gut-microbio


Nonalcoholic Fatty Liver Disease (NAFLD) is a leading cause of hepatic dysfunction, leading to cirrhosis and hepatocellular carcinoma [1,2]. Although NAFLD is caused in part by metabolic dysfunction, inflammatory cell infiltration in the livers of patients with NAFLD suggests that immunological mechanisms are also associated with its pathogenesis and progression. However, the contribution of immune responses to the pathogenesis of NAFLD remains unclear. Recently, cells of the innate immune system, especially Natural Killer T (NKT) cells, have been shown to contribute to NAFLD pathogenesis [3-6]. NKT cells recognize glycolipid antigens through CD1d, triggering either pro- or anti-inflammatory activities [7]. The liver contains a large number of NKT cells [8], which are considered a potential participant in metabolic abnormalities [9,10]. This review summarizes and discusses the role of hepatic NKT cells in the pathogenesis of NAFLD, a hepatic manifestation of a systemic metabolic disorder.

Role of Hepatic NKT Cells

The liver contains a large number of cells of the innate immune system, including Kupffer Cells (KCs) and NKT cells [8]. These cells may act to defend against constant exposure to a variety of toxins and antigens secreted by intestinal bacteria [8,11]. NKT cells are a unique subset of cells, which have both T Cell Receptor (TCR) and surface molecules specific to Natural Killer (NK) cells [12]. NKT cells constitute up to 30% of the intrahepatic lymphocytes in mice, and up to 10% in humans [13]. NKT cells can be divided into types 1 and 2, depending on their interactions with CD1d, a non polymorphic glycolipid antigen-presenting molecule structurally related to the class I Major and Histocompatibility Complex (MHC). Type 1 NKT cells, which express an invariant TCR containing Vα14 in mice and Vα24 in humans, recognize glycolipid in conjunction with CD1d, whereas type 2 NKT cells express a diverse repertoire of TCRs [12].

CD1d is a molecule originally identified on thymocytes and antigen presenting cells [14,15]. In normal livers, CD1d is mainly expressed on KCs, but is also expressed on hepatocytes at a very low level. The expression of CD1d molecule on hepatocytes and bile duct epithelium is up regulated in liver diseases, including NAFLD [16,17]. Type 1 NKT cells are lipid antigen-specific lymphocytes that recognize glycolipid antigens presented on CD1d molecules and produce large amounts of T-helper (Th)1 cytokines, including interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α); Th2 cytokines, including Interleukins (IL)-4 and -10; and Th17 cytokines, including IL-17 and IL-22 [7]. Furthermore, type 1 NKT cells can promote fibro genesis involving the Hedgehog (Hh) pathway and cytokines such as Osteopontin (OPN), leading to Hepatic Stellate Cell (HSC) activation [6]. In contrast, type 2 NKT cells, which are more abundant in humans than in mice, are thought to inhibit type 1 NKT cell mediated liver injury [18].

Collectively, hepatic NKT cells have both proinflammatory and anti-inflammatory functions, and play an important regulatory role in the liver.

NKT cell-CD1d interactions in lipid metabolism dysfunction and systemic disorders

The liver has a central role in lipid metabolism, being involved in lipolysis, lipogenesis and fat storage. CD1d deficient mice fed a high-fat or chorine-deficient diet have been shown to develop hepatic steatosis and glucose intolerance, with glucose intolerance mainly induced by decreased hepatic sensitivity to insulin [19]. CD1d deficiency was also shown to aggravate metabolic parameters, such as glucose homeostasis and hepatic lipid metabolism [19]. Furthermore, CD1d deficient mice fed a high-fat diet were more susceptible to weight gain and fatty liver, along with increased adiposity and greater induction of inflammatory genes in the liver [20]. These findings suggest that NKT cells play a protective role in fat storage and onset of inflammation as the first stage of NAFLD. Hepatic NKT cells are rapidly activated by lipids in a CD1d-dependent fashion [21], and dietary fatty acids have been shown to modulate antigen presentation to hepatic NKT cells in a CD1d-dependent manner [22]. CD1d thus can also modulate insulin resistance and play an important role in lipid metabolism, leading to the induction of hepatic inflammation through antigen presentation to NKT cells. In contrast, CD1d function is regulated by Microsomal Triglyceride Transfer Protein (MTP) [23]. MTP deficiency is associated with loss of CD1d function, leading to impaired activation and reduced number and phenotypic alterations of NKT cells [24,25]. MTP is mainly located in the Endoplasmic Reticulum (ER) and plays a central role in transfer of lipids, including phospholipids, triglycerides and cholesterol. In addition, the transmembrane protein ATP-binding cassette transporter G1 has been shown to play a role in the intracellular transport of cholesterol and to regulate NKT cell development and function [26]. Recently, the metabolic regulator Fnip1 was reported crucial for the development of type 1 NKT cells [27]. Fnip1 is an adaptor protein that interacts with AMPK, an energy-sensing kinase that stimulates mitochondrial biogenesis and autophagy in response to low energy conditions [28]. Thus NKT cells are involved in lipid metabolism and energy regulation and may be associated with systemic metabolic abnormalities.

Recent findings have suggested that NKT cells are involved in systemic metabolic disorders. For example, NKT cells were found to be depleted in adipose tissue of obese individuals [29-31], while restoring NKT cells by adoptive transfer improved glucose handling and induced weight loss [31]. These findings suggest that NKT cells protect against diet-induced obesity and glucose intolerance through the regulation of cytokine production [10]. In addition, CD1d restricted NKT cells were shown to exacerbate atherosclerosis through the production of pro-inflammatory cytokines [32,33]. The development and function of NKT cells are thus regulated by various metabolic mechanisms, affecting metabolism itself and inducing various metabolic disorders Figure 1.

Citation: Tajiri K and Shimizu Y. The Contribution of Hepatic NKT Cells to the Pathogenesis of Nonalcoholic Fatty Liver Diseases. J Hepat Res. 2014;1(3): 1013. ISSN:2381-9057