ReviewRecent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD)
Introduction
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of conditions characterized histologically by hepatic steatosis in individuals without significant alcohol consumption and negative viral, congenital, and autoimmune liver disease markers. Hepatic lipid accumulation results from an imbalance between lipid availability (from circulating lipid uptake or de novo lipogenesis) and lipid disposal (via fatty acid oxidation or triglyceride-rich lipoprotein secretion) and eventually triggers lipoperoxidative stress and hepatic injury. NAFLD is now considered the hepatic manifestation of the metabolic syndrome and has insulin resistance as its hallmark [1], [2]. Previously thought to be benign, it recently became clear NAFLD encompasses a spectrum of liver disease ranging from pure, benign fatty liver to the more severe nonalcoholic steatohepatitis (NASH), a condition that may progress to cirrhosis in up to 25% of patients [3]. Furthermore, NAFLD is emerging as a risk factor for diabetes and cardiovascular disease, independently of insulin resistance, metabolic syndrome, plasma lipid levels and other traditional risk factors [4]. The specific origin of the lipids, mainly triacylglycerol (TAG), accumulating in liver has been unravelled by recent kinetic studies, and identifying the origin of the accumulated TAG and non-esterified fatty acids (NEFA) in the livers of patients with NAFLD may direct prevention and treatment of this condition.
Section snippets
Mechanisms of hepatic lipid accumulation: a kinetic perspective
From a kinetic standpoint, hepatic steatosis develops when there is an imbalance in which fatty acid uptake and de novo synthesis exceed oxidation and resecretion. The sources of fatty acids potentially contributing to fatty liver include (Fig. 1):
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peripheral fat stored in adipose tissue that is delivered to the liver by way of the plasma NEFA pool (pathway 1). Insulin resistance is associated with dysregulation of adipose-derived fatty acid flux in the fasting state, and strong evidence exists
Hepatic non-esterified fatty acid uptake
As summarized above, circulating NEFA, either of dietary or endogenous origin, provide most of the hepatic lipid content in NAFLD. It is therefore essential to gain insight into mechanisms regulating hepatic NEFA uptake from the circulation. Ravikumar et al. observed, by using 13C magnetic resonance spectroscopy, an accelerated postprandial incorporation of dietary fatty acids (FAs) into liver TAG in patients with type 2 diabetes mellitus (4 h vs. 6 h), as well as a 50% higher FA accumulation
Hepatic de novo lipogenesis
According to recent kinetic data,, whereas DNL is only elevated postprandially in healthy subjects (20–30% VLDL–TAG), in NAFLD DNL is elevated in fasting conditions and lacks further postprandial elevation [5], [7], [79]. These observations support the concept of a paradoxically sustained elevation in hepatic lipogenic activity in NAFLD [80]. The regulation of hepatic lipogenesis involves a complex network of nuclear receptors, co-ordinately regulating enzymes involved in different steps of
Hepatic fatty acid oxidative pathways
Different hepatic FA oxidative pathways involved in the pathogenesis of NAFLD have been the subject of several recent reviews and these will be reviewed here briefly [294], [295], [296]. Most FA are metabolized through β-oxidation, which occurs mainly in mitochondria, but also in peroxisomes. A third FA metabolizing pathway is ω-oxidation by members of the cytochrome P450 4A in the endoplasmic reticulum (microsomes). The extramitochondrial FA oxidative pathways become more important in
Regulation of hepatic VLDL assembly and secretion
Recent kinetic studies have pointed out that hepatic triglyceride-rich lipoprotein secretion rate in NAFLD is actually increased in absolute terms, as in other insulin resistant conditions, but is inadequate to match the increased TAG availability in the liver: compared to insulin resistant subjects without a significant liver fat accumulation, subjects with NAFLD failed to further increase VLDL-Tg secretion rate when hepatic Tg infiltration exceeded 10% suggesting the liver of these subjects
Concluding remarks
As it can be seen from this discussion, the pathogenesis of hepatic fat accumulation is very complex and partially understood. Although the excessive flood of free fatty acids to the liver has been traditionally regarded as the key component of NAFLD, little is known The role of hepatic membrane NEFA transporters has only recently emerged, and the complex network regulating de novo lipogenesis has been only partially unravelled. Given the limited efficacy and the long term safety concerns of
Acknowledgement
This work was funded in part by the Piedmont Region Funds Comitato Interministeriale per la Programmazione Economica 2008.
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