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

Abstract

BACKGROUND & AIMS: 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). 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 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. RESULTS: 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). CONCLUSIONS: 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.

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

“…Without altering ChREBP nuclear localization, a diet rich in fructose increases ChREBP binding to DNA nearly 4 fold (Koo et al 2009). Interestingly, dietary fructose more robustly induces DNL in patients with fatty liver disease (Lambert et al 2014). Thus, dietary fructose contributes to the development of NAFLD through increased DNL and NAFLD feeds forward to increase DNL from fructose.…”

PNPLA3 gene in liver diseases

“…VLDL secretion represents the efflux pathway of fat from the liver and, therefore, a reduction in this pathway can partially explain the increase in liver fat found in carriers of the PNPLA3 mutation [86]. Intrahepatic de novo lipogenesis is believed to be a driver of the increase in hepatic fat content [87]. Recently, a study showed that carriers of the rs738409[G] allele have lower de novo lipogenesis as compared to non-carriers due to a reduction in liver SREBP1c mRNA levels [88].…”

Dietary carbohydrate and control of hepatic gene expression: mechanistic links from ATP and phosphate ester homeostasis to the carbohydrate-response element-binding protein

“…T2D is also associated with raised plasma TAG levels and a greater fractional contribution of hepatic de novo lipogenesis (DNL), representing the synthesis of fatty acids from acetyl units (18) , to TAG secretion (19) . In NAFLD, glycerolipid accumulates in hepatocytes because of an imbalance between fatty acid uptake (from NEFA and dietary lipids) plus synthesis (via DNL) relative to fatty acid disposal by mitochondrial β-oxidation plus secretion as TAG in VLDL (20)(21)(22) . In the healthy fasted state, the major sources of substrate for hepatic TAG secretion are NEFA derived from adipose lipolysis with a smaller contribution of NEFA from dietary chylomicrons that escape uptake by extra hepatic tissues and a negligible contribution of DNL (18) .…”

“…In the healthy fasted state, the major sources of substrate for hepatic TAG secretion are NEFA derived from adipose lipolysis with a smaller contribution of NEFA from dietary chylomicrons that escape uptake by extra hepatic tissues and a negligible contribution of DNL (18) . NAFLD is associated with increased fatty acid supply by adipose tissue lipolysis (22) and an increased fractional contribution of DNL to TAG secretion (20)(21)(22) from <5 % in controls to 15-20 % in patients (20,22) . Both the rate of VLDL-TAG secretion derived from DNL and the fractional contribution of DNL to VLDL secretion are elevated in NAFLD and correlate with liver fat content (22) .…”