Non-Alcoholic Fatty Liver Disease: Cause or Effect of Metabolic Syndrome

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease throughout the world. Pathophysiological insights into this disease have recently illustrated that various factors such as insulin resistance, innate immunity, metabolic inflammation, and the microbiota are of relevance. NAFLD, metabolic syndrome (MS), and type 2 diabetes (T2D) share many pathophysiological aspects, and inflammatory processes in the adipose tissue, gut, and liver have evolved to be of exceptional importance. Most of NAFLD patients are obese and encounter a high risk of developing MS and T2D. NAFLD, however, is also highly common in subjects with MS and T2D. Furthermore, reflecting its nature of a multisystem disease, NAFLD is associated with a high prevalence and incidence of cardiovascular and chronic kidney disease. These facts require screening strategies for MS/T2D in NAFLD patients and vice versa. Thus, the question of cause or effect cannot be answered as MS and NAFLD share many pathomechanisms, and at the time of either diagnosis both frequently coexist. This is also reflected by a global prevalence rate of 25% for both NAFLD and MS. For this reason, it is crucial that physicians are aware of the 'unholy liaison' between MS, T2D, and NAFLD.

Keywords: Adiponectin; Cytokines; Inflammation; Insulin resistance; Treatment.

Fig. 1

Potentially involved hepatic pathways in metabolic inflammation and insulin resistance. (1) Interaction of insulin with its receptor results in tyrosine phosphorylation of the IRS and activation of downstream effector mechanisms such as the PI3K/AKT, the PI3K/PKCλ, and ERK pathways (not shown). Various inflammatory networks interfere with insulin signaling. Insulin signaling is attenuated either by inhibitory serine phosphorylation of the IRS or its proteasomal degradation. (2) Engagement of TNFR1 by TNF-α results in activation of IKKβ via TRAF2. Besides IKKβ's outstanding role as activator of NF-κB, the prototypic proinflammatory transcription factor, it has proven a potent catalyst of insulin resistance. (3) The TNF receptor superfamily member RANK and its ligand RANKL activate IKKβ mainly via TRAF6 and promote hepatic insulin resistance. (4) Alternatively, IKKβ activation is initiated by IKKε, a non-canonical NF-κB activator. (5) The obese adipose tissue produces vast amounts of IL-6 which arrives at the liver through the circulation. Activation of the IL-6Ra/gp130 receptor complex results in activation of STAT3, a potent inducer of SOCS molecules. SOCS1 and SOCS3 have been shown to impair insulin signaling by mediating ubiquitin-dependent degradation of the insulin receptor substrate. (6) Expression of SOCS1 and SOCS3 is repressed by HNF1β, a member of the homeodomain-containing superfamily of transcription factors. Translation of HNF1β mRNA is post-transcriptionally regulated by miR-802, a micro RNA that is strongly upregulated in obesity. In a sense, obesity affects SOCS1 and SOCS3 production from two sides, firstly by inducing its expression via IL-6/STAT3 and secondly by suppressing the translation of its inhibitor HNF1β via miR-802. (7) Adipose tissue secretes adiponectin, which exhibits anti-inflammatory properties by inducing IL-10 and IL-1Ra expression. In states of obesity and insulin resistance, however, adipose tissue releases less amounts of adiponectin. Abbreviations: AKT = Protein kinase b; ERK = extracellular signal-regulated kinase; gp130 = interleukin 6 signal transducer; HNF-1β = hepatic nuclear factor 1 beta; IKKβ = inhibitor of kappa light chain gene enhancer in B cell beta kinase; IL-1 = interleukin 1; IL-1Ra = interleukin 1 receptor antagonist; IL-6 = interleukin 6; IL-10 = interleukin 10; IRF-3/7 = interferon regulatory factor 3/7; IRS-1/2 = insulin receptor substrate 1/2; JAK-3 = janus kinase 3; MEK = mitogen-activated protein kinase; MDA-5 = melanoma differentiation-associated gene 5; miR-802 = micro RNA 802; NF-κB = nuclear factor kappa B; RANK = receptor activator of NF kappa B; RANKL = receptor activator of NF kappa B ligand; RIG-1 = retinoic acid-induced gene 1; SOCS-1/3 = suppressor of cytokine signaling 1/3; STAT-3 = signal transducer and activator of transcription 3; TAB-2 = TAK-1-binding protein 2; TAK-1 = transforming growth factor beta-activated kinase 1; TBK-1 = TANK-binding kinase 1; TLR-3 = toll-like receptor 3; TNF-α = tumor necrosis factor alpha; TNFR-1 = tumor necrosis factor receptor 1; TRADD = tumor necrosis factor receptor 1-associated death domain protein; TRAF-2/6 = TNF receptor-associated factor 2/6; PDK1 = pyruvate dehydrogenase kinase isoenzyme 1; PI3K = phosphatidylinositol 3-kinase; PKCλ = protein kinase C gamma.