The lowering of hepatic fatty acid uptake improves liver function and insulin sensitivity without affecting hepatic fat content in humans

Abstract

Iozzo P. The lowering of hepatic fatty acid uptake improves liver function and insulin sensitivity without affecting hepatic fat content in humans. Am J Physiol Endocrinol Metab 295: E413-E419, 2008. First published May 27, 2008 doi:10.1152/ajpendo.00744.2007.-Lipolysis may regulate liver free fatty acid (FFA) uptake and triglyceride accumulation; both are potential causes of insulin resistance and liver damage. We evaluated whether 1) systemic FFA release is the major determinant of liver FFA uptake in fasting humans in vivo and 2) the beneficial metabolic effects of FFA lowering can be explained by a reduction in liver triglyceride content. Sixteen healthy subjects were subdivided in two groups of similar characteristics to undergo positron emission tomography with [11 C]acetate and [ 11 C]palmitate to quantify liver FFA metabolism (n ϭ 8), or magnetic resonance spectroscopy (MRS) to measure hepatic fat content (n ϭ 8), before and after the acute lowering of circulating FFAs by using the antilipolytic agent acipimox. MRS was again repeated after a 1-wk treatment period. Acipimox suppressed FFA levels while stimulating hepatic fractional extraction of FFAs (P Ͻ 0.05). As a result, fasting liver FFA uptake was decreased by 79% (P ϭ 0.0002) in tight association with lipolysis (r ϭ 0.996, P Ͻ 0.0001). The 1-wk treatment induced a significant improvement in systemic (ϩ30%) and liver (ϩ70%) insulin sensitivity (P Ͻ 0.05) and decreased circulating triglycerides (Ϫ20%, P ϭ 0.06) and liver enzymes (ALT Ϫ20%, P ϭ 0.03). No change in liver fat content was observed after either acute or sustained FFA suppression. We conclude that acute and sustained inhibitions of lipolysis and liver FFA uptake fail to deplete liver fat in healthy human subjects. Liver FFA uptake was decreased in proportion to FFA delivery. As a consequence, liver and systemic insulin sensitivity were improved, together with liver function, independently of changes in hepatic triglyceride accumulation. lipolysis; liver metabolism; positron emission tomography; magnetic resonance; acipimox; insulin resistance ACCORDING TO THE OVERFLOW HYPOTHESIS, the provision of fatty acids, as released from adipose tissue to the liver, is responsible for the regulation of liver fat accumulation via hepatic fatty acid uptake (7,14). In turn, liver fat content is proportional to indicators of liver damage such as liver enzymes, suggesting a cause-effect relationship (7,9,14,32). This view implicates that substrate delivery from the circulation plays a dominant, and the intrinsic organ response has a minor, role in the regulation of liver fatty acid uptake. This passive response of the liver remains to be proven in humans in vivo.Lipolysis is not the only source of fatty acids. Lipodystrophy represents an unphysiological state associated with liver steatosis in which endogenous fatty acids may be one major source of triglyceride precursors (25, 27). However, in the normal situation, the meal provides nutrients, suppressing their endogenous release during a time in which hi...

A Dose-Response Elevation in Hepatic Glucose Uptake is Paralleled by Liver Triglyceride Synthesis and Release

“…The present evidence of increased TG content and release, paralleling the mounting HGU and hepatic glucose exposure over the course of the experiments in the absence of extra-hepatic FFA supply suggests an upregulation of de novo lipogenesis, in line with the notion that glucose entering glycolysis can be converted either in glycerol or in acetate for FFA synthesis to provide both structural components of the TG molecule. This reasoning is in accord with our previous observation in humans (21), in whom the acute inhibition of lipolysis was promptly followed by an elevation in liver acetate retention, suggesting the activation of de novo lipogenesis to compensate for FFA deprivation. In this study, the mechanism would be further promoted by the simultaneous provision of excess glucose substrate, which does not rule out that residual FFA delivery-though very small-may have been incorporated in TG.…”

“…So far, studies in humans showing hyperglycemia-induced TG hypersecretion (20) have been conducted during FFA repletion, thus suggesting a diversion of FFA from the catabolic to the anabolic route. We have recently shown that liver FFA uptake relies primarily upon systemic lipolysis, and is very low at plasma FFA levels similar to the ones achieved during hyperglycemia in the current study (21). Consistent with the above concepts, results from our previous studies using PET in a similar animal model during euglycemic hyperinsulinemia (22), together with human studies evaluating the response to the antilipolytic agent acipimox (21), and splanchnic balance investigations in humans during hyperinsulinemia (3) suggested that FFA suppression, whether achieved by hyperinsulinemia or by acipimox inhibits liver TG output due to the lack of substrate.…”

“…We have recently shown that liver FFA uptake relies primarily upon systemic lipolysis, and is very low at plasma FFA levels similar to the ones achieved during hyperglycemia in the current study (21). Consistent with the above concepts, results from our previous studies using PET in a similar animal model during euglycemic hyperinsulinemia (22), together with human studies evaluating the response to the antilipolytic agent acipimox (21), and splanchnic balance investigations in humans during hyperinsulinemia (3) suggested that FFA suppression, whether achieved by hyperinsulinemia or by acipimox inhibits liver TG output due to the lack of substrate. TG are composed of a glycerol backbone binding to FFA chains, and the inhibition of lipolysis translates in the unavailability of both components in the circulation.…”

Triglycerides produced in the livers of fasting rabbits are predominantly stored as opposed to secreted into the plasma

“…The production of VLDL-TGs or liver-secreted TGs has been measured in several studies using tracer methodologies [9-11], and shown to be predominately regulated by the provision of plasma FFAs [12-14]. Under most conditions, the re-esterification of plasma FAs to TGs accounts for the majority of TGs synthesized in liver and the contribution of de novo synthesis of FAs to VLDL-TG production is minor [14].…”

Measuring plasma fatty acid oxidation with intravenous bolus injection of 3H- and 14C-fatty acid

“…Rapid intravenous injection of an FFA tracer is useful when aspects of nonoxidative FA metabolism are investigated. Examples include the incorporation of plasma FAs into VLDL-triglyceride (TG) ( 15,16 ) or the storage/uptake of plasma FAs into tissues (17)(18)(19)(20). In addition, intravenous injections can be more convenient than a continuous infusion, because bolus injections obviate the need to keep the volunteers connected to an infusion pump, thus offering greater mobility and freedom during experimental days.…”