Non-alcoholic fatty liver disease and type 2 diabetes mellitus: the liver disease of our age?

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients.

Keywords: Dysfunctional adipose tissue; Genetics; Hepatocellular cancer; Insulin resistance; Liver cirrhosis; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Obesity; Therapy; Type 2 diabetes mellitus.

Figure 1

Endoplasmatic reticulum stress caused by saturated free fatty acids. Endoplasmatic reticulum stress caused by saturated free fatty acids, via three main mediators [inositol-requiring endoplasmic reticulum-to-nucleus signal kinase 1α (IRE1α), activating transcription factor 6 (ATF6) and RNA-dependent protein kinase (PRK)-like endoplasmic roticulum (ER) kinase (PERK)], results in the activation of c-Jun N-terminal kinase (JNK) and C/ CCAAT/enhancer binding protein (EBP) homologous protein. The sequence of BH3 protein activation based on a sensitizer and an activator group was described by Gurzov and Eizirik in β-cells[62,63]. The sensitizers bind the anti-apoptotic proteins Bcl-2, Bcl-XL and Mcl-1 and release the activators from this bond. JNK both mediates the induction of the sensitizer and the activator BH3 proteins and also activates Bax. Upregulation of Bcl-2 interacting mediator of cell death (BIM) and p53 upregulated modulator of apoptosis (PUMA) was also demonstrated in liver cells as a ruslt of free fatty acid (FFA) induction. Proinflammatory cytokines also activate JNK. ER sterss also results in CHOP actvation and subsequently the activation of the activator BH3 proteins. This complex signaling pathway might link the metabolic (saturated FFAs) stress and the effect of pro-inflammatory cytokines both in the pancreatic β-cell as well as in liver cells.