Calorie Restriction Fights Fatty Liver and Tumor Growth

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Hepatocellular carcinoma (HCC) is a primary liver cancer and a leading cause of death from cancer worldwide. In the U.S. in 2016, liver cancer was the ninth leading cause of cancer-related deaths.1 In 2020, it’s the fifth leading cause of cancer-related deaths in men and the seventh leading cause of cancer deaths in women.2 A recent study in mice concluded that restricting calories could reduce cellular stress, improve insulin signaling and prevent steatosis-associated hepatocarcinogenesis.3

Your liver is located under your right ribs below the lung. It’s the largest internal organ and performs several vital functions. The liver metabolizes some nutrients absorbed from the intestines so they can be used by the body. It also manufactures clotting factors, delivers bile to the intestines and metabolizes alcohol, drugs and waste products.4

Hepatocellular carcinoma is the most common form of primary liver cancer. It has two main growth patterns. In some cases, it starts as a single tumor and only spreads late in the disease. The second type starts as many nodules throughout the organ and is found more often in people with cirrhosis. Without adequate liver function, you will die.

Common conventional treatment approaches include radiation, immunotherapy, chemotherapy and surgical removal of the primary tumor. Current research shows restricting calories helps reduce your risk of HCC. To fully appreciate the results of the study, it’s helpful to know how circadian rhythms affect your liver function.

Your Liver Has Its Own Circadian Rhythm

Your body runs on an internal clock system known as your circadian rhythm. Light exposure to photosensors in your eyes relays a signal to your suprachiasmatic nucleus (SCN) located in the part of the brain called the hypothalamus. The function of your SCN is to synchronize your internal clock, which in turn regulates sleep-wake cycles and other physiological activities.

These include your core body temperature, neuroendocrine function, memory and psychomotor activity. Essentially, the SCN functions as a small pacemaker and is made of multiple circadian oscillator neurons.5 The most important trigger to your SCN is exposure to light.6

The SCN produces an electrical output that uses a specific rhythm, which influences optimal behavioral and physiological mechanisms.7 Several factors can have a negative effect on this, including aging and sleep deprivation.

The SCN is also affected by temperature, food and socialization. Another recent discovery is that your liver has rate-limiting enzymes that are controlled by circadian rhythm.8 Researchers refer to the master clock as the function of your SCN, which regulates your sleep-wake cycles.

However, in the liver, the circadian clock is affected by feeding and fasting to the point where researchers believe it is not connected to your SCN. Animal studies have revealed the metabolic pathways swing independently of other circadian clocks in the body. It affects processes such as NAD+ salvage and glycogen turnover.9

Calorie Restriction May Reset Your Liver

The featured study, published in the journal Liver Cancer, revealed a protective effect from calorie restriction against the development of HCC in animals with nonalcoholic fatty liver disease (NAFLD). The rodents were genetically manipulated so they spontaneously developed fatty liver and tumors.10

They were broken into two groups. The control group was allowed to eat as much as they liked, and the experimental group had their diet limited to 30% fewer calories for 15 months. At the end of the intervention period, the experimental group showed less oxidative stress, downregulation of procancer mediators, improved autophagy and fewer and smaller tumors than the control group. The researchers wrote:11

“Hepatocellular carcinoma (HCC) is one of the common malignancies and leading causes of cancer-related death worldwide. Persistent infection of hepatitis B virus or hepatitis C virus (HCV), ethanol consumption, and genetic metabolic disorders, such as hemochromatosis, Wilson’s disease, glycogen storage disease, and citrin deficiency, are conventional risk factors for HCC.

Recently, worldwide increases in obesity and metabolic syndrome have raised the prevalence of HCC derived from nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), indicating a close relationship between overnutrition and liver tumorigenesis.

These findings support the notion that persistent 30% reduction of daily food intake is beneficial for preventing steatosis-associated hepatocarcinogenesis caused by HCV core protein.”

The results of the current studies supported past research, which also found dawn-to-dusk fasting yielded a significant improvement on serum lipid profiles, oxidative stress and body mass index.12 Researchers called the combination of metabolic syndrome, NAFLD and hepatocellular carcinoma a “rapidly emerging epidemic,” which requires a cost-effective preventive strategy.

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Scientists at Baylor College of Medicine analyzed the data from an animal study finding that the body responded to dietary changes that linked to the circadian system.13 Past research showed how the circadian clock and gut microbiome had independent effects of metabolism. In this study the researchers found, “Disrupting the circadian clock in mouse liver alters the gut microbiome.”14

The change meant the subjects lost less weight. These and other studies have demonstrated the significance of circadian clock control on your liver function. Researchers have found the pathways are affected by eating habits, which can contribute to the development of NAFLD.15

NAFLD Can Progress to Cirrhosis and Cancer

NAFLD is an umbrella term for a range of conditions in the liver that are not associated with alcohol consumption. The main characteristic found with NAFLD is a high amount of fat stored in the liver cells. In some individuals, NAFLD leads to nonalcoholic steatohepatitis (NASH), characterized by inflammation and progression to advanced scarring (cirrhosis) and liver failure.16

Although the condition happens in those who do not drink alcohol, the damage is similar to that seen with heavy alcohol use. NAFLD often causes no symptoms but may be associated with fatigue or discomfort in the right upper abdomen. The primary complication of both NAFLD and NASH is cirrhosis.

The scarring and fibrotic lesions happen as the liver tries to stop the inflammatory process. As this continues, the fibrosis spreads, leading to swelling of the veins in the esophagus, end-stage liver failure and liver cancer.

Although many people with HCC have cirrhosis, up to 20% develop cancer without liver cirrhosis. These cancers are generally found late, in an advanced stage, since many physicians do not use routine screening in people without cirrhosis.17

Dr. Amit Singal, liver cancer program medical director at the University of Texas, spoke at the 2020 Gastrointestinal Cancers Symposium calling for more routine screening in people with NAFLD or NASH, with or without cirrhosis. He called for consistent monitoring since finding people at an early stage places the median survival time over five years.18

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One headline in the American Journal of Managed Care calls NASH and liver cancer “The New Cancer Headline.”19 It is one of several obesogenic cancers driven by “our fat-promoting environment, nutritional policies, and lifestyle” and “is still relatively unfamiliar outside medical literature.”

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Statistics from the U.S. Centers for Disease Control and Prevention show that in 2014, 40% of all cancer diagnoses in the U.S. were from obesogenic cancers.20 The rising rate of weight gain appears to run parallel with the rising rate of weight-related cancer, which increased 7% from 2005 to 2014.

Obesity and Metabolic Syndrome Raise the Risk of NAFLD

Obesity and metabolic syndrome are two risk factors for NAFLD. While researchers are not sure why some with NAFLD go on to develop NASH and others don’t, they have identified risk factors for the progression. Data reveal people with Type 2 diabetes, high levels of triglycerides, metabolic syndrome or obesity have a higher likelihood of progressing from NAFLD to NASH.21

Experts estimate that 25% of adults in the U.S. have NAFLD and of those 20% go on to develop NASH.22 In the Latino community, this percentage is much higher. One study found 45% of Hispanics tested in Dallas, Texas, had hepatic steatosis,23 which is diagnosed when at least 5% of the liver weight is fat.24

More children are also being diagnosed with NAFLD, setting them up for a lifetime of health problems. Before 2006, few people knew children could develop NAFLD. That was the year Dr. Jeffrey Schwimmer, professor of pediatrics at the University of California San Diego, published his findings of 742 pediatric autopsies finding an incidence of 13% with fatty liver disease.25

He found the highest rate of fatty liver disease was in obese children and teens. A subsequent study in 2008 found a gene variant called PNPLA3 could increase the risk of fatty liver disease.26

Michael Goran, Ph.D., director of the diabetes and obesity program at Children’s Hospital of Los Angeles, demonstrated children as young as 8 who had two copies of PNPLA3 and were exposed to high amounts of sugar had 2.36 times more fat in their livers than children without the gene.27

In his current clinical trial, Goran’s team is measuring the impact that education of the child and family has on the development of fatty liver through MRI measurements before and after the intervention.28

Yet, it isn’t just the foods children are consuming that increase their risk of NAFLD. As Goran discovered, high fructose corn syrup (HFCS) from sweetened beverages is passed through breast milk. The team discovered this was positively associated with higher body mass of the infant at 6 months and potentially can predispose the child to obesity and fatty liver disease.29

Steps to Lower Your Risk of Metabolic Syndrome

Metabolic inflexibility is one symptom of metabolic syndrome and poor metabolic health. In the current climate, metabolic inflexibility has been associated with poor outcome from COVID-19.30 Symptoms of metabolic syndrome include:

  • A large waist circumference
  • Prediabetes or Type 2 diabetes
  • High blood pressure or pre-high blood pressure
  • High blood triglycerides
  • Low HDL cholesterol
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The link between poor metabolic health and disease is not new, but it is rising to the forefront in the current pandemic. In my recent interview with Dr. Paul Saladino, he stresses the association between metabolic health and your immune function.

He believes immunometabolism — the connections between metabolism, metabolic health and the immune system — is easily one of the most important, if not the most important, field in emerging medicine. In my interview with Dr. Aseem Malhotra, British cardiologist and author of “The 21 Day Immunity Plan,” he said:

“The real pandemic is poor metabolic health, or metabolic inflexibility. I had become aware, as early on as March, when we were getting data from China and Italy, that there was a clear link between conditions related to excess body fat, in simple terms defined as poor metabolic health, [and] worse outcomes from COVID-19.

We’re talking about conditions like Type 2 diabetes, high blood pressure, heart disease and, of course, obesity. And that data kept emerging. That link was so clear, and it wasn’t just out of the blue.”

The top recommendations Saladino uses to improve your metabolic health, and subsequently lower your risk of infectious disease, obesity and obesogenic cancers, include:

Eliminate processed carbohydrates, sugars, grains and vegetable oils — “I think that from a food perspective, those are the key evils that are really wreaking havoc on our metabolism,” Saladino said in our interview. The worst culprit of them all is probably vegetable oils. “Polyunsaturated vegetable oils are highly oxidizable and very metabolically damaging. So, start with them,” he advises.

For more information about this, see “New Study Tells Why Chicken Is Killing You and Saturated Fat Is Your Friend,” which features Saladino’s interview with science journalist and author Nina Teicholz. Saladino also reviews the mechanisms by which vegetable oils wreck health in greater detail in this interview, so be sure to listen to it in its entirety or read through the transcript.

Eat grass fed animal foods — As noted in a paper published in Nutrients, deficiencies that can compromise immune function include vitamins, A, C, D, E, B2, B6, B12, folate, iron, selenium and zinc.31 These vitamins are primarily found in animal foods, which is why shunning animal foods tends to lead to nutrient deficiencies.

“If you want to have a robust immune system, you want to be metabolically healthy. You don’t want to be insulin-resistant and you need to have nutrient adequacy in your diets. How do you get nutrient adequacy? You get these micronutrients from bioavailable sources in organ meats and in the muscle meat of animals,” Saladino advises.

If you can’t stomach the idea of organ meats, consider using a desiccated supplement, such as those Saladino sells.32

Time-restricted eating — Compressing the window of time in which you eat down to six to eight hours a day, eating your last meal at least three hours before bedtime, is another powerful strategy to improve your insulin sensitivity.

Be more physically active — This can ameliorate and reduce metabolic disease risk markers. Be mindful not to go overboard, since excessive exercise will lower your immune function and put you at increased risk of respiratory infections.

Optimize your sleep.

Reduce your stress.



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