Michael Karin, PhD
Growing evidence suggests that diabetes, cancer, and other diseases are linked at the metabolic level. Basic research is beginning to unravel those metabolic pathways and suggest potential targets for translational research.
One of the clearest links is a web of etiologic factors and metabolic pathways linking liver injury to simple fatty liver disease, cirrhosis, and hepatocellular carcinoma (HCC).
“Hyper-nutrition, excessive alcohol consumption, and exposure to industrial pollutants are leading to increased deposition of fat in the liver,” said Michael Karin, PhD, Professor of Pharmacology at the University of California, San Diego, School of Medicine.
Dr. Karin was one of three researchers to discuss the metabolic links between diabetes, cancer, and other diseases during a Saturday morning symposium at the Scientific Sessions. The progression from fatty liver to HCC is neither simple nor direct, he noted.
Excessive caloric intake can lead to fatty liver, but it takes a second insult, perhaps environmental or excessive alcohol intake, to trigger the progression to hepatic inflammation, steatohepatitis, and HCC.
Using MUP-uPA transgenic mice with a urokinase-type plasminogen activator (uPA) controlled by major urinary protein (MUP) promoter, Dr. Karin found that hepatic lipid cells balloon and die in response to endoplasmic reticulum (ER) stress, prompting scarring and fibrosis.
ER stress triggers de novo lipogenesis in the liver, although the mechanism is not yet clear, he noted. At the same time, hyper-nutrition can upregulate p62, a protein that’s a key component of Mallory-Denk Bodies (MDB). MDBs suppress hepatic inflammation but promote tumor development.
“Our hypothesis is that p62 acts to rescue dying HCC initiating cells from oxidative stress, which allows mutations to accumulate,” Dr. Karin explained. “But without de novo lipogenesis, there would be no accumulation of lipids in the liver and no progression to NASH and HCC.”
Autophagy is a familiar pathway that deposits cytoplasmic constituents into lysosomes. Chaperone-mediated autophagy (CMA) can relieve cellular stress caused by toxins, genetic errors, excessive lipids, nutritional imbalances, and other causes.
The chaperone in CMA is LAMP-2A, one of three related proteins encoded by the lamp2 gene. LAMP-2A levels fall with advancing age but can also be reduced by high-lipid diets, noted Julio Madrigal-Matute, PhD, Postdoctoral Fellow in Developmental and Molecular Biology at Albert Einstein College of Medicine.
Whether caused by age or diet, reductions in LAMP-2A and CMA have dramatic metabolic effects, Dr. Madrigal-Matute said. Mice on a high-carbohydrate diet show significantly greater visceral and subcutaneous fat compared to mice on a high-fat diet. There’s also a whitening of brown adipose tissue. High-fat diets have no effect on LAMP-2.
Knocking out lamp2 promotes an accumulation of circulating lipids and deposition of lipids in the liver of mice on a high-carbohydrate diet, Dr. Madrigal-Matute said. Blocking CMA also promotes dysfunction in glucose metabolism, leaving mice dependent on lipid metabolism. CMA dysfunction also promotes glucose intolerance and insulin resistance.
“We know the combination of elevated glucose, insulin resistance, and glucose intolerance as metabolic syndrome,” Dr. Madrigal-Matute said. “When we have a failure of CMA in the liver, we see profound metabolic dysfunction, including cardiovascular disease, diabetes, obesity, liver disease, and other diseases.”
Branched-chain fatty acid (BCFA) alterations are a newer pathway associated with metabolic dysfunction. BCFAs are endogenous metabolites that link mitochondrial branch-chain amino acid catabolism, lipogenesis, microbiome, and diet with a variety of diseases.
BCFA synthesis is compromised by diet-induced obesity, explained Christian M. Metallo, PhD, Assistant Professor of Bioengineering at the University of California, San Diego. BCFAs correlate significantly with A1C and insulin levels in humans, he added. BCFAs and branched-chain amino acid metabolism are altered in type 2 diabetes, cancer, and other biologic settings.
“BFCAs have been ignored for some time,” Dr. Metallo said. “We need to investigate their role in a number of metabolic dysfunctions.”
