Investigating the Mechanisms by which Intermittent Fasting is Protective of the Liver

The various approaches to restricting calorie intake remain a popular area of scientific study, as periods of low calorie intake produce broadly beneficial effects on the operation of metabolism. They are protective when it comes to the effects of aging. In animal studies, life-long calorie restriction has been shown to slow aging and extend life span. A great deal of work has gone into the production of calorie restriction mimetic drugs that recreate a small fraction of the metabolic response to low calorie diets and fasting, but as of yet none of these are demonstrated to improve on the practice of calorie restriction.

In humans, the evidence suggests that health benefits resulting from even comparatively mild calorie restriction are sizable enough to make it worth considering as a lifestyle choice. That said, the effects on life span are clearly smaller in longer-lived species. Mice live up to 40% longer when calorie restricted, and that is not the case in humans. Exactly why this difference exists remains a mystery, particularly given that the short term metabolic changes that occur when calorie intake is reduced are broadly similar across mammalian species. As today's open access paper notes, when comparing the beneficial changes to the liver that result from calorie restriction, the biochemistry looks very similar in mice and humans.

Intermittent fasting protects against liver inflammation and liver cancer / Drug partially mimics fasting effects

When experimenting with different variants of intermittent fasting, it was found that several parameters determine protection against liver inflammation: The number and duration of fasting cycles play a role, as does the start of the fasting phase. A 5:2 dietary pattern works better than 6:1; 24-hour fasting phases better than 12-hour ones. A particularly unhealthy diet requires more frequent dieting cycles.

Researchers now wanted to find out the molecular background of the response to fasting. To this end, the researchers compared protein composition, metabolic pathways and gene activity in the liver of fasting and non-fasting mice. Two main players responsible for the protective fasting response emerged: the transcription factor PPARα and the enzyme PCK1. The two molecular players work together to increase the breakdown of fatty acids and gluconeogenesis and inhibit the build-up of fats.

The fact that these correlations are not just a mouse phenomenon was shown when tissue samples from metabolic dysfunction-associated steatohepatitis (MASH) patients were examined: Here, too, the researchers found the same molecular pattern with reduced PPARα and PCK1. Are PPARα and PCK1 actually responsible for the beneficial effects of fasting? When both proteins were genetically switched off simultaneously in the liver cells of the mice, intermittent fasting was unable to prevent either chronic inflammation or fibrosis.

The drug pemafibrate mimics the effects of PPARα in the cell. Can the substance also mimic the protective effect of fasting? The researchers investigated this question in mice. Pemafibrate induced some of the favorable metabolic changes that were observed with 5:2 fasting. However, it was only able to partially mimic the protective effects of fasting. "This is hardly surprising, as we can only influence one of the two key players with pemafibrate. Unfortunately, a drug that mimics the effects of PCK1 is not yet available."

A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1

The role and molecular mechanisms of intermittent fasting (IF) in metabolic dysfunction-associated steatohepatitis (MASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen prevents NASH development as well as ameliorates established MASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen blunted MASH-HCC transition when applied therapeutically. The timing, length, and number of fasting cycles as well as the type of NASH diet were critical parameters determining the benefits of fasting.

Combined proteome, transcriptome, and metabolome analyses identified that peroxisome-proliferator-activated receptor alpha (PPARα) and glucocorticoid-signaling-induced PCK1 act co-operatively as hepatic executors of the fasting response. In line with this, PPARα targets and PCK1 were reduced in human MASH. Notably, only fasting initiated during the active phase of mice robustly induced glucocorticoid signaling and free-fatty-acid-induced PPARα signaling. However, hepatocyte-specific glucocorticoid receptor deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of PPARα and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis. Moreover, overexpression of Pck1 alone or together with PPARα in vivo lowered hepatic triglycerides and steatosis. Our data support the notion that the IF 5:2 regimen is a promising intervention against MASH and subsequent liver cancer.

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