Editorial: new insights into the relationship between the intestine and non-alcoholic fatty liver-is "fatty gut" involved in disease progression?

Non‐alcoholic fatty liver disease (NAFLD) is currently the most frequent liver disorder worldwide. There is a high heterogeneity in the natural history of NAFLD, with only a small fraction of patients progressing to end stage liver disease and/or hepatocellular carcinoma. This high variability is partly explained by metabolic comorbidities and genetic risk factors.1 Alteration in the gut microbiota and in the intestinal permeability has also been linked to NAFLD. Robust experimental data suggest endotoxemia is a trigger for hepatic inflammation leading to non‐alcoholic steatohepatitis (NASH) and NAFLD progression.2, 3 However, data from human studies remained controversial.4, 5

Pang and coworkers examined the relationship between markers of endotoxemia and liver damage in patients with NAFLD.6 They measured circulating levels of Lipopolysaccharide (LPS) and LPS binding protein (LBP), a stable biomarker reflecting hepatic LPS exposure in 237 Asian patients with histological NAFLD. First, authors tested whether endotexemia is associated with liver damage, and found that LBP was independently associated with hepatocellular damage and fibrosis, while LPS only with fibrosis. These data lend support to the hypothesis that endotoxemia is involved in the pathogenesis of NASH and promotion of fibrogenesis.

Next, they examined the determinants of endotoxemia. LBP levels were associated with male gender and metabolic risk factors. Carriers of TM6SF2 rs58542926 C>T, encoding for the E167K loss‐of‐function protein variant had also higher LBP levels. The E167K variant predisposes to NAFLD by impairing apoliprotein B (APOB) containing lipoprotein secretion by hepatocytes. Indeed, the mutation is associated with reduced fasting circulating lipoprotein concentration.7, 8 TM6SF2 silencing in the liver results in steatosis due to decreased secretion of very low‐density lipoproteins (VLDL)‐associated lipids,7 possibly by decreasing the lipidation of VLDL.9 Importantly, TM6SF2 is also highly expressed in the intestine, which plays an important role in post‐prandial lipid absorption by secreting chylomicrons, and lipid absorption was modestly impaired in Tm6sf2‐/‐ mice.9 Therefore, TM6SF2 variant may also reduce the ability to secrete chylomicrons by enterocytes in humans. In parallel, a retention of chylomicrons occurs in loss‐of‐function APOB mutations10 also increasing the risk of to steatosis and progressive liver disease.1

It would thus be tempting to speculate that lipid accumulation in enterocytes, or “fatty gut” due to the diet, insulin resistance or genetic factors causes a damage to the epithelial barrier, increased leaking of bacterial products and consequently liver damage. The potential mechanism linking the TM6SF2 mutation with endotexemia and progressive liver damage is presented in Figure 1. To prove this model enterocyte fat accumulation, increased intestinal permeability and absorption of intestinal products should be shown in carriers of the TM6SF2 variant and APOB loss‐of‐function mutations.

Figure 1

Putative model for the mechanism linking the TM6SF2 E167K variant and APOB loss‐of‐function (LOF) mutations with endotoxemia and progressive NAFLD

Collectively, these new data are consistent with the hypothesis that endotoxemia is involved in the pathogenesis of progressive NAFLD, with potential therapeutic implications. Human genetics may help shedding light into the relationship between altered intestinal environment and liver disease.

Funding Information

None.