The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis. (October 2016) - Herman, Mark A.
Abstract : Epidemiological studies link fructose consumption with metabolic disease, an association attributable in part to fructose-mediated lipogenesis. The mechanisms governing fructose-induced lipogenesis and disease remain debated. Acutely, fructose increases de novo lipogenesis through the efficient and uninhibited action of ketohexokinase and aldolase B which yields substrates for fatty-acid synthesis. Chronic fructose consumption further enhances the capacity for hepatic fructose metabolism by activating several key transcription factors (i.e., SREBP1c and ChREBP) which augment the expression of lipogenic enzymes, increasing lipogenesis and further compounding hypertriglyceridemia and hepatic steatosis. Hepatic insulin resistance develops from diacylglycerol–PKCɛ-mediated impairment of insulin signaling and possibly additional mechanisms. Initiatives that decrease fructose consumption and therapies that block fructose-mediated lipogenesis will be necessary to avert future metabolic pandemics. Trends: Fructose comprises ∼50% of the dietary sugars sucrose and high-fructose corn syrup, and when consumed in excess exacerbates cardiometabolic risk factors including dyslipidemia, fatty liver disease, and insulin resistance. Ketohexokinase (KHK) may be a therapeutic target. Complete knockout of all KHK isoforms prevents fructose-induced disease. By contrast, selective knockout of the ubiquitous, low-activity KHK-A isoform exacerbates fructose-induced disease, possibly by increasing flux through the KHK-C isoform expressed in key metabolic tissues such as liver. Fructose contributes to lipogenesis and associated pathologies, including steatosis, dyslipidemia, and hepatic insulin resistance, both by providing substrate and coordinating the expression of lipogenic enzymes via SREBP1c and ChREBP. Limiting fructose intake and regulating fructose metabolism may represent a promising therapeutic strategy to reduce cardiometabolic risk factors.