Rohit Kohli

FXR is a molecular target for the effects of vertical sleeve gastrectomy

Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.

High-fructose, medium chain trans fat diet induces liver fibrosis and elevates plasma coenzyme Q9 in a novel murine model of obesity and nonalcoholic steatohepatitis†

Diets high in saturated fat and fructose have been implicated in the development of obesity and nonalcoholic steatohepatitis (NASH) in humans. We hypothesized that mice exposed to a similar diet would develop NASH with fibrosis associated with increased hepatic oxidative stress that would be further reflected by increased plasma levels of the respiratory chain component, oxidized coenzyme Q9 (oxCoQ9). Adult male C57Bl/6 mice were randomly assigned to chow, high‐fat (HF), or high‐fat high‐carbohydrate (HFHC) diets for 16 weeks. The chow and HF mice had free access to pure water, whereas the HFHC group received water with 55% fructose and 45% sucrose (wt/vol). The HFHC and HF groups had increased body weight, body fat mass, fasting glucose, and were insulin‐resistant compared with chow mice. HF and HFHC consumed similar calories. Hepatic triglyceride content, plasma alanine aminotransferase, and liver weight were significantly increased in HF and HFHC mice compared with chow mice. Plasma cholesterol (P < 0.001), histological hepatic fibrosis, liver hydroxyproline content (P = 0.006), collagen 1 messenger RNA (P = 0.003), CD11b‐F4/80+Gr1+ monocytes (P < 0.0001), transforming growth factor β1 mRNA (P = 0.04), and α‐smooth muscle actin messenger RNA (P = 0.001) levels were significantly increased in HFHC mice. Hepatic oxidative stress, as indicated by liver superoxide expression (P = 0.002), 4‐hydroxynonenal, and plasma oxCoQ9 (P < 0.001) levels, was highest in HFHC mice. Conclusion: These findings demonstrate that nongenetically modified mice maintained on an HFHC diet in addition to developing obesity have increased hepatic ROS and a NASH‐like phenotype with significant fibrosis. Plasma oxCoQ9 correlated with fibrosis progression. The mechanism of fibrosis may involve fructose inducing increased ROS associated with CD11b+F4/80+Gr1+ hepatic macrophage aggregation, resulting in transforming growth factor β1–signaled collagen deposition and histologically visible hepatic fibrosis. (HEPATOLOGY 2010)

Weight Loss Induced by Roux-en-Y Gastric Bypass But Not Laparoscopic Adjustable Gastric Banding Increases Circulating Bile Acids

CONTEXT It has been hypothesized that increased plasma bile acids (BAs) contribute to metabolic improvements after Roux-en-Y gastric bypass (RYGB) surgery by the G protein-coupled receptor TGR5-mediated effects on glucagon-like peptide-1 secretion and thyroid hormones. OBJECTIVE The objective of this study was to evaluate the importance of bariatric surgery-induced alterations in BA physiology on factors that regulate glucose homeostasis (insulin secretion and sensitivity) and energy metabolism (resting energy expenditure and thyroid hormone axis). DESIGN, PARTICIPANTS, INTERVENTION, AND MAIN OUTCOME MEASURE: Eighteen extremely obese subjects were studied before and after 20% weight loss, induced by either laparoscopic adjustable gastric banding (LAGB) (n = 10) or RYGB surgery (n = 8). RESULTS Plasma BAs more than doubled after RYGB [fasting: 1.08 (0.26-1.42) to 2.28 (1.59-3.28) μmol/L, P = .03; postprandial: 2.46 ± 1.59 to 6.00 ± 2.75 μmol/L, P = .01] but were either lower or did not change after LAGB [fasting: 1.80 (1.49-2.19) to 0.92 (0.73-1.15) μmol/L, P = .02; postprandial: 3.71 ± 2.61 to 2.82 ± 1.75 μmol/L, P = .14]. Skeletal muscle expression of TGR5 targets, Kir6.2 and cyclooxygenase IV, increased after RYGB but not LAGB. Surgery-induced changes in BAs were associated with increased peak postprandial plasma glucagon-like peptide-1 (r(2) = 0.509, P = .001) and decreased serum TSH (r(2) = 0.562, P < .001) but did not correlate with the change in insulin response to a meal (r(2) = 0.013, P = .658), insulin sensitivity (assessed as insulin stimulated glucose disposal during a hyperinsulinemic-euglycemic clamp procedure) (r(2) = 0.001, P = .995), or resting energy expenditure (r(2) = 0.004, P = .807). CONCLUSIONS Compared with LAGB, RYGB increases circulating BAs and TGR5 signaling, but this increase in BAs is not a significant predictor of changes in glucose homeostasis or energy metabolism.

Nonalcoholic Steatohepatitis in Children: A Multicenter Clinicopathological Study

Nonalcoholic fatty liver disease (NAFLD) may have distinct histological features in children and adults, but to date limited data are available on the spectrum and significance of histological lesions in pediatric patients. We conducted a multicenter study of children with well‐characterized, biopsy‐proven NAFLD to (1) assess the presence and significance of a constellation of histological lesions and (2) identify clinical and laboratory predictors of disease severity. One hundred thirty children with NAFLD seen from 1995 to 2007 in five centers in the United States and Canada were studied. Clinical and laboratory data were collected. Slides stained with hematoxylin‐eosin and trichrome were evaluated by two liver pathologists. The NAFLD activity score (NAS) and the pattern of liver injury (type 1 or adult versus type 2 or pediatric nonalcoholic steatohepatitis [NASH]) were recorded. Fibrosis was staged using a published 7‐point scale. The median age was 12 years (range, 4‐18 years); 63% were boys, and 52% were Caucasian. Fibrosis was present in 87% of patients; of these, stage 3 (bridging fibrosis) was present in 20%. No patient had cirrhosis. The median NAS was 4. Overlapping features of both type 1 (adult pattern) and type 2 (pediatric pattern) NASH were found in 82% of patients. Compared with patients with no or mild fibrosis, those with significant fibrosis were more likely to have higher lobular and portal inflammation scores (P < 0.01), perisinusoidal fibrosis (P < 0.001), and NAS ≥5 (P < 0.005). Serum aspartate aminotransferase levels were the only clinical or laboratory data that independently predicted severity of fibrosis (P = 0.003). Conclusion: Our results highlight the limitations of published proposals to classify pediatric NAFLD, and identified histological lesions associated with progressive disease. (HEPATOLOGY 2009.)

Mechanisms of lipotoxicity in NAFLD and clinical implications.

ABSTRACT With the epidemic of childhood obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in pediatrics. NAFLD is strongly associated with insulin resistance and increased level of serum free fatty acids (FFAs). FFAs have direct hepatotoxicity through the induction of an endoplasmic reticulum stress response and subsequently activation of the mitochondrial pathway of cell death. FFAs may also result in lysosomal dysfunction and alter death receptor gene expression. Lipoapoptosis is a key pathogenic process in NAFLD, and correlates with progressive inflammation, and fibrosis. Accumulation of triglyceride in the liver results from uptake and esterification of FFAs by the hepatocyte, and is less likely to be hepatotoxic per se. To date, there are no proven effective therapies that halt NAFLD progression or unfortunately improve prognosis in children. The cellular mechanisms of lipotoxicity are complex but provide potential therapeutic targets for NAFLD. In this review we discuss several potential therapeutic opportunities in detail including inhibition of apoptosis, c-Jun-N-terminal kinase, and endoplasmic reticulum stress pathways.

Vertical sleeve gastrectomy reduces hepatic steatosis while increasing serum bile acids in a weight-loss-independent manner

Our objective was to investigate the role of bile acids in hepatic steatosis reduction after vertical sleeve gastrectomy (VSG).

A Surgical Model in Male Obese Rats Uncovers Protective Effects of Bile Acids Post-Bariatric Surgery

Bariatric surgery elevates serum bile acids. Conjugated bile acid administration, such as tauroursodeoxycholic acid (TUDCA), improves insulin sensitivity, whereas short-circuiting bile acid circulation through ileal interposition surgery in rats raises TUDCA levels. We hypothesized that bariatric surgery outcomes could be recapitulated by short circuiting the normal enterohepatic bile circulation. We established a model wherein male obese rats underwent either bile diversion (BD) or Sham (SH) surgery. The BD group had a catheter inserted into the common bile duct and its distal end anchored into the middistal jejunum for 4-5 weeks. Glucose tolerance, insulin and glucagon-like peptide-1 (GLP-1) response, hepatic steatosis, and endoplasmic reticulum (ER) stress were measured. Rats post-BD lost significantly more weight than the SH rats. BD rats gained less fat mass after surgery. BD rats had improved glucose tolerance, increased higher postprandial glucagon-like peptide-1 response and serum bile acids but less liver steatosis. Serum bile acid levels including TUDCA concentrations were higher in BD compared to SH pair-fed rats. Fecal bile acid levels were not different. Liver ER stress (C/EBP homologous protein mRNA and pJNK protein) was decreased in BD rats. Bile acid gavage (TUDCA/ursodeoxycholic acid [UDCA]) in diet-induced obese rats, elevated serum TUDCA and concomitantly reduced hepatic steatosis and ER stress (C/EBP homologous protein mRNA). These data demonstrate the ability of alterations in bile acids to recapitulate important metabolic improvements seen after bariatric surgery. Further, our work establishes a model for focused study of bile acids in the context of bariatric surgery that may lead to the identification of therapeutics for metabolic disease.

IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice

Inflammation plays a central pathogenic role in the pernicious metabolic and end‐organ sequelae of obesity. Among these sequelae, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the developed world. The twinned observations that obesity is associated with increased activation of the interleukin (IL)‐17 axis and that this axis can regulate liver damage in diverse contexts prompted us to address the role of IL‐17RA signaling in the progression of NAFLD. We further examined whether microbe‐driven IL‐17A regulated NAFLD development and progression. We show here that IL‐17RA−/− mice respond to high‐fat diet stress with significantly greater weight gain, visceral adiposity, and hepatic steatosis than wild‐type controls. However, obesity‐driven lipid accumulation was uncoupled from its end‐organ consequences in IL‐17RA−/− mice, which exhibited decreased steatohepatitis, nicotinamide adenine dinucleotide phosphate (NADPH)‐oxidase enzyme expression, and hepatocellular damage. Neutralization of IL‐17A significantly reduced obesity‐driven hepatocellular damage in wild‐type mice. Further, colonization of mice with segmented filamentous bacteria (SFB), a commensal that induces IL‐17A production, exacerbated obesity‐induced hepatocellular damage. In contrast, SFB depletion protected from obesity‐induced hepatocellular damage. Conclusion: These data indicate that obesity‐driven activation of the IL‐17 axis is central to the development and progression of NAFLD to steatohepatitis and identify the IL‐17 pathway as a novel therapeutic target in this condition. (Hepatology 2014;59:1830–1839)

Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats

Fibroblast growth factor-19 (FGF19) and its rodent ortholog, FGF15, are hormones produced in the distal small intestine and secreted into the circulation after a meal. In addition to controlling the enterohepatic circulation of bile acids, FGF15/19 also regulates systemic lipid and glucose metabolism. In these experiments we investigated the hypothesis that, like other gut-derived postprandial hormones, FGF15/19 can act in the central nervous system to elicit its metabolic effects. We found that FGF-receptors 1 and 4 are present in rat hypothalamus, and that their expression was reduced by up to 60% in high-fat fed rats relative to lean controls. Consistent with a potential role for brain FGF15/19 signaling to regulate energy and glucose homeostasis, and with a previous report that intracerebroventricular (i.c.v.) administration of FGF19 increases energy expenditure, we report that acute i.c.v. FGF19 reduces 24-h food intake and body weight, and acutely improves glucose tolerance. Conversely, i.c.v. administration of an FGF-receptor inhibitor increases food intake and impairs glucose tolerance, suggesting a physiological role for brain FGF receptor signaling. Together, these findings identify the central nervous system as a potentially important target for the beneficial effects of FGF19 in the treatment of obesity and diabetes.

Use of Magnetic Resonance Elastography to Assess Hepatic Fibrosis in Children with Chronic Liver Disease

Management of pediatric chronic liver disease is limited by lack of validated noninvasive biomarkers of histologic severity. We demonstrate that magnetic resonance elastography is feasible and accurate in detecting significant hepatic fibrosis in a case series of 35 children with chronic liver disease, including severely obese children.