1,2-sn-Diacylglycerol accumulates in choline-deficient liver. A possible mechanism of hepatic carcinogenesis via alteration in protein kinase C activity?

Choline deficiency is associated with triacylglycerol accumulation in the liver, and is the only nutritional state known to trigger hepatic cancer spontaneously. In two different experiments, rats were pair-fed for 6 weeks with control (0.2% choline), or choline-deficient (CD) (0.002% choline) diets. Hepatic choline and phosphocholine declined in CD animals to 54% and 16% of control levels, respectively. In control livers, 1,2-sn-diacylglycerol (1,2-sn-DAG) concentration was (in nmol/g wet wt) 144 (± 25; mean ± SE); while in CD livers it was 792 (± 140) in the first experiment. In the second experiment the values were 375 (± 26) and 1147 (± 74), respectively. 1,2-sn-DAG, a precursor of triacylglycerol, is an endogenous activator of protein kinase C (PKC). PKC is the presumed site of action of the tumor-promoting phorbol esters. We suggest that the 1,2-sn-DAG accumulating in CD liver could bind PKC, altering its activity, and thus contribute to the carcinogenic effect of CD diets

The underconsumed and underappreciated essential nutrient

Choline has been recognized as an essential nutrient by the Food and Nutrition Board of the National Academies of Medicine since 1998. Its metabolites have structural, metabolic, and regulatory roles within the body. Humans can endogenously produce small amounts of choline via the hepatic phosphatidylethanolamine N-methyltransferase pathway. However, the nutrient must be consumed exogenously to prevent signs of deficiency. The Adequate Intake (AI) for choline was calculated at a time when dietary intakes across the populationwere unknown for the nutrient. Unlike the traditional National Academy of Medicine approach of calculating an AI based on observed or experimentally determined approximations or estimates of intake by a group (or groups) of healthy individuals, calculation of the AI for choline was informed in part by a depletionrepletion study in adultmen who, upon becoming deficient, developed signs of liver damage. The AI for other gender and life-stage groups was calculated based on standard reference weights, except for infants 0 to 6 months, whose AI reflects the observedmean intake from consuming human breast milk. Recent analyses indicate that large portions of the population (ie, approximately 90% of Americans), including most pregnant and lactating women, are well below the AI for choline. Moreover, the food patterns recommended by the 2015-2020 Dietary Guidelines for Americans are currently insufficient to meet the AI for choline in most age-sex groups. An individual's requirement for choline is dependent on common genetic variants in genes required for choline, folate, and 1-carbon metabolism, potentially increasing more than one-third of the population's susceptibly to organ dysfunction. The American Medical Association and American Academy of Pediatrics have both recently reaffirmed the importance of choline during pregnancy and lactation. Newand emerging evidence suggests that maternal choline intake during pregnancy, and possibly lactation, has lasting beneficial neurocognitive effects on the offspring. Because choline is found predominantly in animal-derived foods, vegetarians and vegans may have a greater risk for inadequacy. With the 2020-2025 Dietary Guidelines for Americans recommending expansion of dietary information for pregnant women, and the inclusion of recommendations for infants and toddlers 0 to 2 years, better communication of the role that choline plays, particularly in the area of neurocognitive development, is critical. This narrative review summarizes the peer-reviewed literature and discussions from the 2018 Choline Science Summit, held in Washington, DC, in February 2018

Deletion of murine choline dehydrogenase results in diminished sperm motility

Choline dehydrogenase (CHDH) catalyzes the conversion of choline to betaine, an important methyl donor and organic osmolyte. We have previously identified single nucleotide polymorphisms (SNPs) in the human CHDH gene that, when present, seem to alter the activity of the CHDH enzyme. These SNPs occur frequently in humans. We created a Chdh-/- mouse to determine the functional effects of mutations that result in decreased CHDH activity. Chdh deletion did not affect fetal viability or alter growth or survival of these mice. Only one of eleven Chdh-/- males was able to reproduce. Loss of CHDH activity resulted in decreased testicular betaine and increased choline and PCho concentrations. Chdh+/+ and Chdh-/- mice produced comparable amounts of sperm; the impaired fertility was due to diminished sperm motility in the Chdh-/- males. Transmission electron microscopy revealed abnormal mitochondrial morphology in Chdh-/- sperm. ATP content, total mitochondrial dehydrogenase activity and inner mitochondrial membrane polarization were all significantly reduced in sperm from Chdh -/- animals. Mitochondrial changes were also detected in liver, kidney, heart, and testis tissues. We suggest that men who have SNPs in CHDH that decrease the activity of the CHDH enzyme could have decreased sperm motility and fertility