Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease

Abstract

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.

Keywords: Diabetes; Fatty Acid Kinetics; Lipid Metabolism; Obesity.

Figure 1.. Dynamics of plasma glucose, insulin, and fatty acids

Data are presented as mean ± SEM. The 18h study period was divided into three segments for analysis: 1800 to midnight (post-evening meal), midnight to 0600 (at night), and 0600 to 1200 (during the extended fast). Panels A displays glucose and (B) insulin concentrations, which were not different between the groups during any of the segments. Panel C: postprandial changes in total plasma free fatty acid (FFA) concentrations (total; circles), those derived from adipose lipolysis (adipose; squares) or from evening-meal spillover (evening meal; triangles) in subjects with High liver fat (HighLF, filled symbols) and Low liver fat (LowLF, open symbols). P-values represent significant differences between the HighLF and LowLF groups for the FFA sources within the designated time period (determined by repeated measures ANOVA).

Figure 2.. Proportion of fatty acid sources becoming labeled in TRL-TG from midnight to noon in subjects with low or high liver fat

Data represent the proportions of fatty acids arising from the (A) evening meal, (B) plasma FFA pool, (C) de novo lipogenesis, and (D) the proportion of total fatty acid sources accounted for in TRL particles at the end of the experiment. Values reported on the right edge of panels A-D represent the average of the last two measurements taken in the fasting state (e.g., 1030 and 1145). Data are presented as mean ± SEM; asterisks denote significant differences between groups at individual time points (P<.05); open circles = Low liver fat (LowLF) group; filled circles = High liver fat (HighLF) group.

Figure 3.. Absolute contributions of fatty acid sources to fasting VLDL-TG in subjects with low or high liver fat and the relationships between liver fat with de novo lipogenesis

A) The absolute concentrations of fatty acids arising from the evening meal, plasma FFA pool, de novo lipogenesis, and the amount remaining unlabeled in fasting VLDL-TG particles. Values represent the mean group data from each subject in which the last two measurements were taken in the fasting state (e.g., 1030 and 1145) and data from these two time points were averaged for that subject. Relationships between liver fat content and de novo lipogenesis represented as B) newly-synthesized fatty acid in VLDL-TG in units of mmol/L and C) as a fraction of VLDL-TG from lipogenesis (%). Open circles, Low liver fat (LF) group; filled circles, High liver fat (LF) group.