Gastroenterology

Gastroenterology

Volume 146, Issue 3, March 2014, Pages 726-735
Gastroenterology

Original Research
Full Report: Clinical—Liver
Increased De Novo Lipogenesis Is a Distinct Characteristic of Individuals With Nonalcoholic Fatty Liver Disease

https://doi.org/10.1053/j.gastro.2013.11.049Get rights and content

Background & Aims

There have been few studies of 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 subjects with NAFLD and those without, matched for metabolic factors (controls).

Methods

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 (LowLF, n = 11) of liver fat. 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 (nonesterified) fatty acid (FFA) and triacylglycerol flux and lipogenesis.

Results

Subjects with HighLF (18.4% ± 3.6%) had higher plasma levels of FFAs during the nighttime and higher 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 FFAs (414 ± 195 μmol/min for HighLF vs 358 ± 105 μmol/min for LowLF; P = .41) or production of very-low-density lipoprotein triacylglycerol from FFAs (4.06 ± 2.57 μmol/min vs 4.34 ± 1.82 μmol/min; P = .77). In 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).

Conclusions

By administering isotopes to subjects with NAFLD and control subjects, we confirmed that those with NAFLD have increased synthesis of fatty acids. Subjects with NAFLD also had higher nocturnal plasma levels of FFAs and did not suppress the contribution from de novo lipogenesis on fasting. These findings indicate that lipogenesis might be a therapeutic target for NAFLD.

Section snippets

Subjects and Methods

The methods are briefly described here and have been reported previously.14, 31, 32 A detailed description of the study design, laboratory procedures, and calculations is provided in Supplementary Methods. Research subjects were recruited from local community health fairs and physician referrals to determine the role of metabolic syndrome in the development of NAFLD.1 The initial screening criteria included characteristics of metabolic syndrome,33 and liver enzyme levels were measured to

Results

Subjects were separated phenotypically as having LowLF or HighLF1 (Table 1). The LowLF and HighLF groups were matched for anthropometric and plasma biochemistry data except for fasting insulin concentrations, which were higher in the HighLF group, as expected.39 This higher level of insulin resulted in a greater calculated AdipoIR, an index of adipose insulin resistance,6 in subjects with HighLF (Table 1). Given the differences in body composition, anthropometric variables for men and women

Discussion

The present study represents the first direct confirmation of the significant role of de novo lipogenesis in the etiology of fatty liver disease. Compared with subjects with LowLF, those with HighLF had a doubling of the fractional contribution from de novo lipogenesis to VLDL-FA (10.1% ± 6.7% vs 23.2% ± 7.9%, respectively; P < .001), a 3-fold higher rate of production of VLDL-TG from lipogenesis, accounted for through extended labeling of the lipogenic pathway, and a positive association

Acknowledgments

The authors thank the research subjects for their participation; the staff of the Clinical and Translational Research Center and Dora Bradford, RN-C, WHNP, for recruitment and screening of the subjects and excellent patient care; Maressa Valdez, RD, for subject recruitment, clinical coordination, and data collection; Joseph Lee, BS, Yelena Hovhannisyan, MS, and Kimberly Borke, MD, for data generation, analysis, and management; Drs Jay Horton and Scott Grundy for support; Dr Elizabeth Murphy for

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    Author names in bold designate shared co-first authorship.

    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by National Institutes of Health (NIH) grant RL1DK081187 (to E.J.P.), the Task Force for Obesity Research at UT Southwestern/NIH grant UL1DE019584, and the Clinical Translational Science Award, National Center for Advancing Translational Sciences/NIH grant UL1-RR024982.

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