Article

Increased De Novo Lipogenesis Is a Distinct Characteristic of Individuals With Nonalcoholic Fatty Liver Disease

University of Texas Southwestern Medical Center. Electronic address: .
Gastroenterology (Impact Factor: 16.72). 12/2013; 146(3). DOI: 10.1053/j.gastro.2013.11.049
Source: PubMed

ABSTRACT

There have been few studies on the role of de novo lipogenesis in the development of nonalcoholic fatty liver disease (NAFLD). We used isotope analyses to compare de novo lipogenesis and fatty acid flux between individuals with NAFLD and those without, matched for metabolic factors (controls).
We studied subjects with metabolic syndrome and/or levels of alanine aminotransferase and aspartate aminotransferase >30 mU/L, using magnetic resonance spectroscopy to identify those with high levels (HighLF, n=13) or low levels of intrahepatic triacylglycerol (LowLF, n=11). Clinical and demographic information was collected from all participants, and insulin sensitivity was measured using the insulin-modified intravenous glucose tolerance test. Stable isotopes were administered and gas chromatography with mass spectrometry was used to analyze free (non-esterified) fatty acid (FFA) and triacylglycerol flux and lipogenesis.
Individuals with HighLF (18.4%±3.6%) had higher plasma levels of FFA during the nighttime and concentrations of insulin than subjects with LowLF (3.1%±2.7%; P=.04 and P<.001, respectively). No differences were observed between groups in adipose flux of FFA (414±195 μmol/min for HighLF vs 358±105 μmol/min for LowLF; P=.41) or production of very low-density lipoprotein triacylglycerols from FFA (4.06±2.57 μmol/min vs 4.34±1.82 μmol/min; P=.77). By contrast, subjects with HighLF had more than 3-fold higher rates of de novo fatty acid synthesis than subjects with LowLF (2.57±1.53 μmol/min vs 0.78±0.42 μmol/min; P=.001). As a percentage of triacylglycerol palmitate, de novo lipogenesis was 2-fold higher in subjects with HighLF (23.2%±7.9% vs 10.1%±6.7%; P<.001); this level was independently associated with the level of intrahepatic triacylglycerol (r=0.53; P=.007).
By administering isotopes to individuals with NAFLD and control subjects, we confirmed that those with NAFLD increase synthesis of fatty acids. Subjects with NAFLD also had higher nocturnal plasma levels of FFA and did not suppress the contribution from de novo lipogenesis upon fasting. These findings indicate that lipogenesis might be a therapeutic target for NAFLD.

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Available from: Elizabeth J Parks, Nov 21, 2014
    • "Increased proportion of palmitic acid in TG in individuals with NASH is related to elevated activity of DNL[48]. Accordingly, increased activity of DNL has previously been reported in NAFLD49505152and it has been suggested to have a role in hepatic fat accumulation[52,53]. Moreover, increased DNL activity might partly explain why individuals with NASH have high proportions of serum SFAs, which in turn may lead to elevated proportion of monounsaturated FAs as the activity of SCD1 increases[48]. "
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    • "However, the precise molecular mechanisms of pathogenesis and disease progression are only partially understood. While excess release of fatty acids by lipolysis in adipose tissue due to insulin resistance is generally accepted as contributing to the etiology of hepatic steatosis (Sanyal 2005), a significant role of increased hepatic de novo lipogenesis (DNL) was only very recently proven (Lambert et al. 2014). By acting as key metabolic sensors, nuclear receptors control hepatic glucose and lipid metabolism. "
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