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


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.

Download full-text


Available from: Elizabeth J Parks, Nov 21, 2014
64 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dysregulation of lipid homeostasis is intimately associated with obesity, type 2 diabetes and cardiovascular diseases. Sterol regulatory-element binding proteins (SREBPs) are the master regulators of lipid biosynthesis. Previous studies have shown that the conserved transcriptional cofactor Mediator complex is critically required for the SREBP transcriptional activity and recruitment of the Mediator complex to the SREBP transactivation domains (TADs) is through the MED15-KIX domain. Recently, we have synthesized several boron-containing small molecules. Among these novel compounds, BF175 can specifically block the binding of MED15-KIX to SREBP1a-TAD in vitro, resulting in an inhibition of the SREBP transcriptional activity and a decrease of SREBP-target gene expression in cultured hepatocytes. Furthermore, BF175 can improve lipid homeostasis in the mouse model of diet-induced obesity. Compared to the control, BF175 treatment decreased the expression of SREBP-target genes in mouse livers, and decreased hepatic and blood levels of lipids. These results suggest that blocking the interaction between SREBP-TADs and the Mediator complex by small molecules may represent a novel approach for treating diseases with aberrant lipid homeostasis.
    Diabetes 03/2014; 63(7). DOI:10.2337/db13-0835 · 8.10 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Accumulating evidence indicates that obesity is closely associated with an increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease. Obesity results from an imbalance between food intake and energy expenditure, which leads to an excessive accumulation of adipose tissue. Adipose tissue is now recognized not only as a main site of storage of excess energy derived from food intake but also as an endocrine organ. The expansion of adipose tissue produces a number of bioactive substances, known as adipocytokines or adipokines, which trigger chronic low-grade inflammation and interact with a range of processes in many different organs. Although the precise mechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excess adipose tissue and adipose tissue dysfunction can contribute to the development of obesity-related metabolic diseases. In this review, we focus on the role of several adipokines associated with obesity and the potential impact on obesity-related metabolic diseases. Multiple lines evidence provides valuable insights into the roles of adipokines in the development of obesity and its metabolic complications. Further research is still required to fully understand the mechanisms underlying the metabolic actions of a few newly identified adipokines.
    International Journal of Molecular Sciences 04/2014; 15(4):6184-223. DOI:10.3390/ijms15046184 · 2.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Metabolic syndrome is a cluster of metabolic abnormalities that identifies people at risk of diabetes and cardiovascular disease, whereas non-alcoholic fatty liver disease (NAFLD) is defined as a disorder with excess fat in the liver due to non-alcoholic causes. Two key components of metabolic syndrome, glucose and triglycerides, are overproduced by the fatty liver. The liver is therefore a key determinant of metabolic abnormalities. The prevalence of both metabolic syndrome and NAFLD increases with obesity. Other acquired causes for both disorders include excessive intake of simple sugars and physical inactivity. Both disorders predict type 2 diabetes, cardiovascular disease, non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma. Because metabolic syndrome can be defined in many different ways, NAFLD might be a more direct predictor of these diseases. Half of people with NAFLD carry at least one variant (G) allele at rs738409 in the PNPLA3 gene, which is associated with high liver fat content. Steatosis in PNPLA3-associated NAFLD is not accompanied by features of metabolic syndrome. All forms of NAFLD increase the risk of NASH, cirrhosis, and hepatocellular carcinoma.
    04/2014; 2(11). DOI:10.1016/S2213-8587(14)70032-4
Show more