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Metabolic control of acetyl-CoA production.

ATP-citrate lyase (ACL) and acetyl-CoA synthetase 1 (ACECS1) generate acetyl-CoA outside of mitochondria in mammalian cells, and this acetyl-CoA can be used for protein acetylation and lipogenesis^22,³⁹. Both enzymes are metabolically regulated. ACL produces acetyl-CoA from citrate, which is exported from mitochondria under nutrient-replete conditions. Most of the acetyl-CoA produced by ACL is originally derived from glucose or glutamine carbon (see Box 1). This provides a dynamic range of acetyl-CoA production in response to nutrient availability and metabolism. By contrast, ACECS1, which generates acetyl-CoA from acetate, is activated under nutrient-limited conditions by the NAD⁺-dependent deacetylase sirtuin 1 (SIRT1)³³. Thus, depending on metabolic conditions, ACL and ACECS1 may each play greater or lesser parts in producing acetyl-CoA.

A two-way street: reciprocal regulation of metabolism and signalling

In this integrated model, we propose that protein modifications such as acetylation and glycosylation serve as indicators of nutrient sufficiency to the cell to signal that conditions are optimal for growth. Nutrient-sensitive acetylation of histones (and other transcriptional regulators) can regulate the expression of genes involved in cell growth⁴³. Acetylation of the M2 isoform of pyruvate kinase (PKM2) promotes its degradation⁴⁷, probably facilitating the diversion of glucose carbon to upstream biosynthetic pathways, such as the hexosamine biosynthetic pathway. Increased UDP-N-acetylglucosamine (UDP-GlcNAc) levels produced in this pathway promote increased N-glycan branching, enhancing surface expression of glycoproteins such as growth factor receptors (GFRs)⁶¹. Enhanced GFR presence on the cell surface promotes downstream signalling when ligands are present, completing a positive feedback loop. Increased UDP-GlcNAc levels also promote O-GlcNAc protein modification, which is crucial for normal cell cycle regulation, among other roles^58,^73,^74,^75,⁷⁶. ACL, ATP-citrate lyase; F6P, fructose-6-phosphate; GLUT, glucose transporter; mTORC1, mammalian target of rapamycin complex 1; OGT, O-GlcNAc transferase; PEP, phosphoenolpyruvate; PI3K, phosphoinositide 3-kinase.

http://www.nature.com/nrm/journal/v13/n4/fig_tab/nrm3305_F1.html

Why High-Fiber Diets May Help Weight Loss

Nutritionists have long known that eating more fiber is a good idea. It helps digestion, and evidence suggests it curbs appetite.

Now, new research on animals suggests that one reason fiber makes you less hungry is because after you eat it, your body produces a chemical called acetate — also found in vinegar — which changes brain cells that control hunger.

In experiments, mice and rats that were fed a high-fiber diet had more acetate in their guts, and those given acetate directly into the colon ate less than animals not given the compound, according to the study.

“There’s a big body of literature that suggests metabolic activity of [gut bacteria] releases [hunger-suppressing] hormones,” said study researcher Gary Frost, a professor of nutrition and dietetics at Imperial College, London. “Our paper shows that it’s the short-chain fatty acid acetate, produced by biota in the colon.”

In mammals – both rodents and humans – fiber is digested by bacteria in the colon, which release various chemicals as they work. Fiber gets broken down into acetate, among other things.

In one set of experiments, the researchers fed a group of mice a diet that was high in a type of fiber called inulin (not to be confused with the hormone insulin), which is found in foods such as bananas and garlic. Another group of mice was fed a diet low in that type of fiber.

After two months, the mice with the high-inulin diet had gained less weight, and an analysis of their colon content showed more acetate compared with the mice on the low-inulin diet.

Other studies suggested that fiber affects hunger by changing hormone levels, but Frost’s team noted that their own previous work had found certain kinds of brain cells in the hypothalamus fired more often after high-fiber diets, and the hormones involved in appetite suppression actually suppress this kind of neuronal activity.

So in a second set of experiments, the researchers gave mice and rats acetate intravenously and via the colon. The acetate was tagged with radioactive carbon, so the researchers could track its path through the body with a PET scan.

About 3 percent of the acetate stayed in the bloodstream, and made its way to the brains of the mice, specifically their hypothalamuses, which regulate appetite.

This shows that acetate affects the brain and regulates hunger, the researchers said.

So does this mean drinking vinegar can help you lose weight? Frost noted that to get the same effect as eating fiber, a person would have to drink a lot, because vinegar is digested and much of the acetate in it breaks down. “You’d have to drink enough for it to get to the brain,” he said. Drinking so much vinegar would be unhealthy — the chemical is quite acidic.

Frost said he and his team plan to do more research to tease out exactly how big the effect of fiber on hunger is. “With dietary fiber the actual effects are complex, it’s one of a number of systems that have effects on appetite, and there are others.”

http://www.livescience.com/45225-why-fiber-helps-weight-loss.html

Fiber’s Cancer-Fighting Effect Depends on Gut Bacteria

Bacteria
Credit: Dreamstime

SAN DIEGO — A high-fiber diet may protect against colon cancer, but only if you have the right gut bacteria, a new study in mice suggests.

In the study, mice were fed either a low- or high-fiber diet, and some had a type of bacteria in their gut that ferments fiber into a chemical called butyrate, while others did not. All of the mice were then given a cancer-causing chemical so that they would develop colon tumors.

The number of tumors was 75 percent lower in mice that were fed a high-fiber diet and had the butyrate-producing bacteria in their guts, compared with the other mice. However, the high-fiber diet by itself, without the butyrate-producing bacteria, did not protect against colon cancer; nor did a low-fiber diet with butyrate-producing bacteria.

http://www.livescience.com/44665-fiber-colon-cancer-gut-bacteria.html

Benefits of Prebiotics to Human Health

The microbiota profile associated with the production and use of SCFAs may be affected by age, as well as immunity status and stress condition, which might also have an influence on the colonic transit time [77]. Lower levels of SCFAs in healthy individuals’ feces may be an indication of a better absorption rather than a lower production [78]. In fact, most of the SCFAs (acetate, butyrate, and propionate) that rise in the large intestine as metabolites from bacterial fermentation enter the systemic metabolism through the blood circulation [79].

Other products, such as pyruvate and lactate, can also be further transformed into SCFAs [80]. This is the reason for these organic acids not being found in high amounts in the large intestine when searching for the end-products of the metabolism of a prebiotic (fiber). These SCFAs and lactate are known for their beneficial effects. For example, propionate is used in the liver, where it was suggested to exert some function on cholesterol synthesis, thus decreasing its levels in the liver and in the blood. On the other hand, acetate is transformed by muscle and brain cells and may be a precursor for cholesterol synthesis, while butyrate is metabolized in colonic cells. Here it seems to play a role in maintaining the integrity of the colonic mucosa by positively interfering in the activity of epithelial cells and also in cell apoptosis [21,81,82] (Figure 1). Additionally, there could be a significant increase in total SCFAs, but when they are considered individually, such differences may not exist for each of the SCFA levels.

However, the end-products of proteolytic or peptolytic fermentation (amines, phenols, ammonia) may exert harmful effects by triggering some diseases and bowel disorders [83]. Nevertheless, health-promoting bacteria of microbiota may exert positive effects on such diseases (IBDs and irritable bowel syndrome, IBS) [76]. Some toxins may also be produced [74].