*Geek Box: Origins of Liver Fat

*Geek Box: Pathways of Hepatic Fat

In the fasted state, adipose tissue lipolysis (i.e., the breakdown of stored TGs and release of NEFA) constitutes the primary endogenous pathway delivering NEFA to the liver. As humans spend a majority of the day in the fed state, however, it is important to look at the various pathways through which fatty acids may be delivered to the liver from dietary intake. There are three main pathways:

  • chylomicron-spillover NEFA
  • chylomicron remnants
  • de novo lipogenesis [DNL].

The chylomicron pathways are derived from dietary fat. Dietary fat in the form of triglycerides [TGs] enters circulation from the intestines packaged into chylomicrons, large triglyceride-rich lipoproteins which constitute the pathway of dietary fat intake. TGs in chylomicrons are hydrolysed [i.e., broken down] into NEFA by a group of enzymes known as lipases, in particular lipoprotein lipase [LPL].

A proportion of fatty acids mobilised from LPL acting on chylomicron-TGs are not taken up by adipose tissue, and “spillover” into the pool of circulating NEFA which contributes the greatest proportion of fatty acids to intra-hepatic triglycerides [IHTG]. In general, the contribution of systemic NEFA to hepatic fatty acids may be in the region of 45-75%. This pathway of LPL-mediated breakdown of chylomicron-TGs also produces what are known as “remnants”, formed when the hydrolysis of chylomicron-TGs results in a smaller lipoprotein, i.e., a chylomicron-remnant. These chylomicron-remnants are taken up by the liver, and the remaining TGs in the remnant particle may be repackaged into VLDL. Over a 24-hr period, the contribution of NEFA derived from chylomicron-remnants has been shown to be greater than the contribution of chylomicron spillover NEFA.

The final exogenous pathway is DNL, where fatty acids are synthesised in the liver from non-fat precursor sources, primarily from excess dietary carbohydrate,  in particular free sugars [proteins contribute very little to DNL]. The contribution of DNL to hepatic NEFA in metabolically healthy individuals is relatively small at <5%, however, the presence of fatty liver substantially modifies the rate of DNL, which may be up  to ~22-24% in individuals with NAFLD. In addition, insulin resistance strongly modifies post-prandial DNL, which increases in individuals with elevated insulin levels.

In sum, hepatic fat originates from endogenous systemic NEFA derived from adipose tissue and splanchnic lipolysis, exogenous dietary fatty acids derived from chylomicron spillover or chylomicron remnants, and the de novo synthesis of fatty acid from non-fat precursors, in particular carbohydrate. The respective contribution of fatty acids to VLDL-TG have been shown to be in the region of 75-84% from the systemic NEFA pool, 12-39% from dietary fatty acids, and 5-22% from DNL, with the range of contributions reflecting variability due to metabolic health of the individual, in addition to dietary composition.