Excessive Hepatic Mitochondrial TCA Cycle and Gluconeogenesis in Humans with Nonalcoholic Fatty Liver Disease

Abstract

Summary Approximately one-third of the U.S. population has nonalcoholic fatty liver disease (NAFLD), a condition closely associated with insulin resistance and increased risk of liver injury. Dysregulated mitochondrial metabolism is central in these disorders, but the manner and degree of dysregulation are disputed. This study tested whether humans with NAFLD have abnormal in vivo hepatic mitochondrial metabolism. Subjects with low (3.0%) and high (17%) intrahepatic triglyceride (IHTG) were studied using 2H and 13C tracers to evaluate systemic lipolysis, hepatic glucose production, and mitochondrial pathways (TCA cycle, anaplerosis, and ketogenesis). Individuals with NAFLD had 50% higher rates of lipolysis and 30% higher rates of gluconeogenesis. There was a positive correlation between IHTG content and both mitochondrial oxidative and anaplerotic fluxes. These data indicate that mitochondrial oxidative metabolism is ∼2-fold greater in those with NAFLD, providing a potential link between IHTG content, oxidative stress, and liver damage.

In Vivohyperpolarized carbon-13 magnetic resonance spectroscopy reveals increased pyruvate carboxylase flux in an insulin-resistant mouse model

“…Therefore, it is unsurprising that a recent 13 C isotopomer study found a 2-fold increase of hepatic TCA cycle flux in patients with nonalcoholic fatty liver disease. 26 Because only pyruvate that enters the TCA cycle through PC produces a net increase in cycle intermediates, whereas pyruvate entering through PDH is restricted to energy production only, 27 the elevated PC flux and OAA pool observed in diabetic mice must have also catered to the increased FAS demand. This agrees with our recent observation in the hypertrophied heart, in which a larger 13 C-citrate signal (from increased pyruvate anaplerosis) was recorded.…”

Protein kinase STK25 controls lipid partitioning in hepatocytes and correlates with liver fat content in humans

“…It is generally accepted that mitochondrial β-oxidation plays an important role in liver steatosis and hepatic insulin resistance, although the nature of this role is still under debate. Increased hepatic mitochondrial oxidation has been observed in patients and rodents with fatty liver [23,24], which likely reflects a metabolic adaptation to elevated lipid burden to limit further fat accumulation. Indeed, the development of fatty liver and hepatic insulin resistance in response to high-fat feeding in rats can be prevented by increasing mitochondrial β-oxidation [25][26][27][28].…”

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

“…This may explain the correlation between raised fractional DNL and raised TAG secretion rate (21) . DNL may represent a spill over of acetyl-units (as citrate efflux from mitochondria) as suggested by the association between intrahepatic lipid and flux through tricarboxylic acid cycle oxidation plus anaplerosis (and increased gluconeogenic flux), in the absence of elevated ketone body production (24) .…”

“…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) . Other hepatic metabolic abnormalities in NAFLD include impaired suppression of hepatic glucose production by insulin (23) ; elevated gluconeogenesis and increased flux through tricarboxylic acid cycle oxidation and anaplerosis, without increased turnover of ketone bodies (24) . A key paradox is that despite a greater fractional contribution of DNL to TAG secretion in NAFLD, the net flux through DNL is very small (<5 %) relative to carbohydrate turnover (25) .…”