Hepatic fatty acid synthesis and partitioning: the effect of metabolic and nutritional state

Abstract

When we consume dietary fat, a series of complex metabolic processes ensures that fatty acids are absorbed, transported around the body and used/stored appropriately. The liver is a central metabolic organ within the human body and has a major role in regulating fat and carbohydrate metabolism. Studying hepatic metabolism in human subjects is challenging; the use of stable isotope tracers and measurement of particles or molecules secreted by the liver such as VLDL-TAG and 3-hydroxybutyrate offers the best insight into postprandial hepatic fatty acid metabolism in human subjects. Diet derived fatty acids are taken up by the liver and mix with fatty acids coming from the lipolysis of adipose tissue, and those already present in the liver (cytosolic TAG) and fatty acids synthesised de novo within the liver from non-lipid precursors (known as de novo lipogenesis). Fatty acids are removed from the liver by secretion as VLDL-TAG and oxidation. Perturbations in these processes have the potential to impact on metabolic health. Whether fatty acids are partitioned towards oxidation or esterification pathways appears to be dependent on a number of metabolic factors; not least ambient insulin concentrations. Moreover, along with the phenotype and lifestyle factors (e.g. habitual diet) of an individual, it is becoming apparent that the composition of the diet (macronutrient and fatty acid composition) may play pivotal roles in determining if intra-hepatic fat accumulates, although what remains to be elucidated is the influence these nutrients have on intra-hepatic fatty acid synthesis and partitioning. Liver: VLDL-TAG: Fatty acid partitioning: Fatty acid oxidationThe liver has a major role in regulating metabolic homeostasis; it is a central cross-road for fatty acid and glucose metabolism. It serves as an intermediary organ between dietary (exogenous) and endogenous energy sources and other extra-hepatic organs/tissues that consume energy; perturbations in its metabolism have the potential to impact widely on metabolic disease risk. In health, the liver rapidly adapts to alterations in nutritional state and the nutrient fluxes that occur from a fasted (postabsorptive) to fed (postprandial) state. However, the deposition of fat (ectopic fat) in nonadipose tissues such as the liver has been suggested to be an important factor in the development of obesity related metabolic abnormalities (1,2) . The net retention of intra-hepatic fat is a prerequisite for the development of non-alcoholic fatty liver disease (NAFLD) (3) , which is now recognised as the hepatic manifestation of the metabolic syndrome (2) . A well-recognised risk factor for NAFLD is obesity, and both are risk factors for more severe metabolic diseases such as type-2 diabetes and CVD; the prevalence of NAFLD parallels that of type-2 diabetes (4) . Why the liver starts to accumulate fat is not well understood but is likely to occur when fatty acid input and synthesis exceed the liver's capacity for removal (e.g. for secretion or oxidation) (5)(6)(7) . The intra-hepa...

Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids

“…In vivo evidence of retention of labeled 13 C-18:2 PUFAs in the human liver in PNPLA3 148MM compared with PNPLA3 148II group. Dietary FAs are transported from the intestinal lumen to the circulation in chylomicron-TGs, which then undergo hydrolysis and are taken up by the liver (12). VLDL-TGs are produced exclusively by the liver (12).…”

“…Dietary FAs are transported from the intestinal lumen to the circulation in chylomicron-TGs, which then undergo hydrolysis and are taken up by the liver (12). VLDL-TGs are produced exclusively by the liver (12). Thus, to compare handling of PUFAs and SFAs in the liver, we calculated their ratio in VLDL-TGs and chylomicron-TGs.…”

Challenging metabolic tissues with fructose: tissue‐specific and sex‐specific responses

“…For the DNL pathway to be upregulated, insulin activates the transcription factor sterol regulatory element‐binding protein 1c (SREBP‐1c), which enhances the transcription of genes required for fatty acid and TAG synthesis (Brown & Goldstein, ). Fasting hepatic DNL has been reported to be up to ∼10% in healthy adults and significantly higher (up to 22%) in individuals with insulin resistance/NAFLD (Hodson, ).…”

Mitochondrial Lipid Homeostasis at the Crossroads of Liver and Heart Diseases

“…Under the pressure of continuous impaired FA (fatty acid) metabolism, the liver accumulates a significant amount of lipids that lead to NAFLD development. The main feature of NAFLD is an accumulation of hepatic TGs, which could be caused by internal (impaired FAO, VLDL synthesis and export), external (certain genetic background and environmental conditions) or behavioural (exceed FAs from the diet, circulation or adipose tissue, lack of physical activities) triggers [51,52]. An imbalance between imported/exported and synthesized/processed FAs results in hepatic lipid accumulation, hepatosteatosis and IR, which is further stimulating de novo hepatic lipogenesis making this vicious cycle complete [53].…”