Dr. Kohli and his team of scientists have focused their work on obesity-related fatty liver disease (NASH). One key advance was when back in 2010, when Dr. Kohli’s laboratory highlighted the role of fructose, such as that present in food containing high fructose corn syrup (HFCS), in triggering injury and scarring within the liver.
Additionally, Dr. Kohli’s team has developed a surgical model in mice that is now used by researchers around the world to better understand how weight loss surgeries improve obesity and its associated morbidities, such as NASH. The understanding as to how weight loss surgery such as the vertical sleeve gastrectomy (VSG) works was previously thought to be based on the dogmas of restriction and malabsorption. We have shown that bile acid signaling is critical to the success of these surgical procedures. Now we use the VSG surgical technique on diet-induced obese mice, and try to further understand the role of bile acids and bile acid signaling targets such as the farnesoid X receptor (FXR) pathway to better understand the specific mechanism behind the success of these surgical procedures.
Current Research Projects:
Bariatric surgery remains the most effective and durable treatment option for obesity to date. More importantly, beyond weight loss, bariatric procedures have many advantageous metabolic effects including resolution of advanced obesity related liver disease or nonalcoholic steatohepatitis (NASH). In our NIH funded proposal Dr. Kohli’s laboratory will focus on the mechanisms of NASH resolution after weight loss surgery using an obese mouse model.
Bile Acids Induce Proliferation (Pink) of intestinal cells
Reactive oxygen species (Red) production by liver cells in response to high concentrations of free fatty acids
Left to right: Dong Xi, MD, PhD, Rosa-Maria Salazar-Gonzalez, PhD, Rohit Kohli, MBBS, MS, Jashdeep Bhattarjee, PhD
Impact of Bariatric Surgery on NAFLD and Bile Acid Physiology
Our primary area of research is the impact of bariatric surgery on non-alcoholic fatty liver disease (NAFLD) and bile acid physiology. In this area of research the laboratory works to understand the mechanism and impact of bariatric surgical procedures such as sleeve gastrectomy and roux-en-Y gastric bypass on nonalcoholic steatohepatitis (NASH) and other co-morbidities of obesity. Our research involves using small animal models of common and experimental bariatric procedures to study the role of bile acids in the improvements seen after bariatric surgery.
We began this work by using an experimental bariatric procedure called ileal transposition in rats (see figure 1), but we’ve progressed to murine vertical sleeve gastrectomy (VSG), specifically its effects on intestinal adaptation (see figure 2). Recently, we are also using ileal enteroid cultures (see figure 3) for investigating the mechanistic role of bile acid triggered signaling pathways including the farnesoid x receptor (FXR) and its downstream effectors such as fibroblast growth factor (FGF19).
Figure 1 - Impact of Bariatric Surgery on NAFLD and Bile acid physiology
Figure 2 - Apical Sodium Bile acid Transporter (ASBT) staining of the terminal ileum sections with ASBT antibody (green fluorescence). Stained area was significantly larger in VSG compared to Sham-operated mice.
Figure 3 - Ileal enteroid cultures: Intestinal tissue from C57bl/6 mice was used to grow enteroids. This representative image shows Edu incorporation (yellow fluorescence) in ileal derived murine enteroid villous cells suggesting proliferative response.
The secondary area is non-alcoholic fatty liver disease (NAFLD) pathogenesis. We focus on the role of lipotoxicity, reactive oxygen species, inflammatory pathways and endoplasmic reticulum stress in the generation and regulation of the extreme stage of this disease; nonalcoholic steatohepatitis (NASH). Our laboratory has contributed to the field by highlighting the role of fructose in triggering above mentioned oxidative injury and inflammation which results in fibrosis within the liver. We introduced a novel yet simple dietary model of murine NASH wherein the disease is recapitulated with all its essential hepatic histologic features (steatosis, inflammation and fibrosis) in a milieu of obesity and insulin resistance (See Figure 1).
- Our lab introduced a novel yet simple dietary mouse model where we recapitulated obesity related liver disease with all its essential features (steatosis, inflammation and fibrosis) in a milieu of obesity and insulin resistance. Hepatology 2010 Sep;52(3):934-44
- We next showed that weight loss induced by gastric bypass in humans with obesity increases circulating bile acids. J Clin Endo Metab, 2013 Apr;98(4):E708-12.
- Next in work published in the journal Nature, our group showed that mice that lack a specific bile acid nuclear receptor (FXR) underwent weight loss surgery and did not lose weight as expected. Nature, May 8 2014;509(7499):183-8.
- Recent Publications
1: Africa JA, Behling CA, Brunt EM, Zhang N, Luo Y, Wells A, Hou J, Belt PH, Kohil R, Lavine JE, Molleston JP, Newton KP, Whitington PF, Schwimmer JB; Nonalcoholic Steatohepatitis Clinical Research Network.. In Children With Nonalcoholic Fatty Liver Disease, Zone 1 Steatosis Is Associated With Advanced Fibrosis. Clinical Gastroenterology Hepatology. 2017 Mar 7. pii: S1542-3565(17)30261-6. doi: 10.1016/j.cgh.2017.02.030. [Epub ahead of print] PubMed PMID: 28286193.
2: Patton A, Khan FH, Kohli R. Impact of Fibroblast Growth Factors 19 and 21 in Bariatric Metabolism. Digestive Diseases. 2017;35(3):191-196. doi: 10.1159/000450910. Epub 2017 Mar 1. PubMed PMID: 28249286.
3: Vos MB, Abrams SH, Barlow SE, Caprio S, Daniels SR, Kohli R, Mouzaki M, Sathya P, Schwimmer JB, Sundaram SS, Xanthakos SA. NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). Journal of Pediatric Gastroenterology and Nutrition. 2017 Feb;64(2):319-334. doi:10.1097/MPG.0000000000001482. PubMed PMID: 28107283.
4: Saubermann LJ, Deneau M, Falcone RA, Murray KF, Ali S, Kohli R, Ekong UD, Valentino PL, Grossman AB, Rand EB, Jonas MM, Saeed SA, Kamath BM. Hepatic Issues and Complications Associated With Inflammatory Bowel Disease: A Clinical Report From the NASPGHAN Inflammatory Bowel Disease and Hepatology Committees. Journal of Pediatric Gastroenterology and Nutrition. 2017 Apr;64(4):639-652. doi: 10.1097/MPG.0000000000001492. PubMed PMID: 27984347.
5: Khan FH, Shaw L, Zhang W, Salazar Gonzalez RM, Mowery S, Oehrle M, Zhao X, Jenkins T, Setchell KD, Inge TH, Kohli R. Fibroblast growth factor 21 correlates with weight loss after vertical sleeve gastrectomy in adolescents. Obesity (Silver Spring). 2016 Nov;24(11):2377-2383. doi: 10.1002/oby.21658. Epub 2016 Sep 12. PubMed PMID: 27615057.
6: Averin K, Bucuvalas J, Alonso MH, Kohli R, Heubi JE, Johnson ND, Goldstein BH. Treatment of Inferior Vena Cava Obstruction Following Pediatric Liver Transplantation: Novel Use of a Customized Endovascular Stent. Journal of Pediatrics. 2017 Jan;180:256-260. doi: 10.1016/j.jpeds.2016.09.051. Epub 2016 Oct 25. PubMed PMID: 27793336.
7: Schwimmer JB, Lavine JE, Wilson LA, Neuschwander-Tetri BA, Xanthakos SA, Kohli R, Barlow SE, Vos MB, Karpen SJ, Molleston JP, Whitington PF, Rosenthal P, Jain AK, Murray KF, Brunt EM, Kleiner DE, Van Natta ML, Clark JM, Tonascia J, Doo E; NASH CRN. In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores. Gastroenterology. 2016 Dec;151(6):1141-1154.e9. doi: 10.1053/Gastroenterology.2016.08.027. Epub 2016 Aug 26. PubMed PMID: 27569726; PubMed Central PMCID: PMC5124386.
8: Trout AT, Dillman JR, Xanthakos S, Kohli R, Sprague G, Serai S, Mahley AD, Podberesky DJ. Prospective Assessment of Correlation between US Acoustic Radiation Force Impulse and MR Elastography in a Pediatric Population: Dispersion of US Shear-Wave Speed Measurement Matters. Radiology. 2016 Nov;281(2):544-552. Epub 2016 May 26. PubMed PMID: 27228332.
9: Samuel EM, Bernstein K, Xanthakos SA, Kohli R. Alpha 1-antitrypsin levels can differentiate allelic phenotypes. Digestive and Liver Disease. 2016 Dec;48(12):1510-1511. doi: 10.1016/j.dld.2016.09.011. Epub 2016 Sep 23. PubMed PMID: 27720697.
10: Himes RW, Barlow SE, Bove K, Quintanilla NM, Sheridan R, Kohli R. Lysosomal Acid Lipase Deficiency Unmasked in Two Children With Nonalcoholic Fatty Liver Disease. Pediatrics. 2016 Oct;138(4). pii: e20160214. Epub 2016 Sep 13. PubMed PMID: 27624512.
11: Kelly D, Johnson N, Veldtman G, Kocoshis S, Kohli R. "Twin" Biliary Trees in a Patient with Heterotaxy Syndrome. Journal of Pediatric Gastroenterology and Nutrition. 2016 Aug 6. [Epub ahead of print] PubMed PMID: 27504813.
12: Khan FH, Kohli R. Bariatric Surgery: The Rise and Fall of Bile Acids. Surgery for Obesity and Related Diseases. 2016 May;12(4):770-1. doi: 10.1016/j.soard.2015.12.027. Epub 2015 Dec 22. PubMed PMID: 26965154.
13: Kohli R, Sunduram S, Mouzaki M, Ali S, Sathya P, Abrams S, Xanthakos SA, Vos M, Schwimmer JB. Pediatric Nonalcoholic Fatty Liver Disease: A Report from the Expert Committee on Nonalcoholic Fatty Liver Disease (ECON). Journal of Pediatrics. 2016 May;172:9-13. doi: 10.1016/j.jpeds.2015.12.016. Epub 2016 Jan 1. PubMed PMID:26749112; PubMed Central PMCID: PMC4846502.